Novel 11β-substituted-19-nor-steroids

ABSTRACT

Novel 19-nor-steroids of the formula ##STR1## wherein R 1  is an organic group of 1 to 18 carbon atoms optionally containing at leat one heteroatom with the atom immediately adjacent the 11-carbon atom being carbon, R 2  is a hydrocarbon of 1 to 8 carbon atoms, X is the remainder of a pentagonal or hexagonal ring optionally substituted and optionally containing one unsaturated bond, the A and B rings are selected from the group consisting of ##STR2## R&#39; and R&#34; are individually selected from the group consisting of hydrogen, --CN and alkyl of 1 to 4 carbon atoms, R x  is selected from the group consisting of hydrogen and OR e , R e  is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms and acyl, R a  may be in the E or Z positions as indicated by the wavy line and is selected from the group consisting of ##STR3## and acyloxy, R a  &#39; and R a  &#34; are alkyl of 1 to 4 carbon atoms or taken together with the nitrogen atom form a heterocycle of 5 to 6 chain members optionally containing another heteroatom with the proviso that when A and B are ##STR4## wherein R&#39; and R&#34; are both hydrogen, R 1  contain at least one nitrogen, phosphorus or silicium atom and when A and B are ##STR5## R 1  is not a linear alkyl and their non-toxic, pharmaceutically acceptable acid addition salts having a remarkable antiglucocorticoid activity, their preparation and novel intermediates.

PRIOR APPLICATIONS

The present application is a combined CIP application of U.S. patentapplication Ser. No. 693,682 filed Jan. 22, 1985 now U.S. Pat. No.4,634,695 which in turn is a continuation-in-part of copendingapplication Ser. No. 614,440 filed May 25, 1984 now U.S. Pat. No.4,519,946 which in turn is a division of application Ser. No. 595,267filed Mar. 30, 1984 now abandoned which in turn is a division of U.S.patent application Ser. No. 386,967, filed June 10, 1982, now U.S. Pat.No. 4,447,424 which is a continuation-in-part of U.S. patent applicationSer. No. 338,077 filed Jan. 8, 1982, now U.S. Pat. No. 4,386,085 andU.S. patent application Ser. No. 760,703 filed July 30, 1985 which inturn is a division of U.S. patent application Ser. No. 501,373 filedJune 6, 1983, now U.S. Pat. No. 4,547,493.

STATE OF THE ART

U.S. Pat. No. 4,233,296 describes steroids being substituted in the11-position with substituents other than the present formula whichrequire an organic substitutent containing a nitrogen, phosphorous orsilicon atom. U.S. Pat. No. 3,190,796 describes steroids having ahydroxyl in the 11β-position. Schonemann et al European Journal ofMedicin Chemistry Chimica Therapeutica, Vol. 15, No. 4, (July, Aug. 1980pp. 333-335]describes steroids substituted in the 11β-position with CH₂═, --CH₂ OH and ##STR6##

Commonly assigned U.S. Pat. No. 4,272,530 and copending U.S. patentapplication Ser. No. 469,042 filed Feb. 23, 1983 describe relatedsteroids of different structures.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I and their non-toxic, pharmaceutically acceptable acid additionsalts and a novel process for their preparation and novel intermediates.

It, is another object of the invention to provide novelantiglucooorticoid compositions and a novel method of inducingantiglucocorticoidal activity in blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of 19-nor-steroids of the formula ##STR7## wherein R₁ is anorganic group of 1 to 18 carbon atoms optionally containing at least oneheteroatom with the atom immediately adjacent the 11-carbon atom beingcarbon, R₂ is a hydrocarbon of 1 to 8 carbon atoms, X is the remainderof a pentagonal or hexagonal ring optionally substituted and optionallycontaining one unsaturated --bond, the A and B rings are selected fromthe group consisting of ##STR8## R' and R" are individually selectedfrom the group consisting of hydrogen, --CN and alkyl of 1 to 4 carbonatoms--R_(x) is selected from the group consisting of hydrogen andOR_(e), R_(e) is selected from the group consisting of hydrogen,optionally substituted alkyl of 1 to 6 carbon atoms and acyl, R_(a) maybe in the E or Z positions as indicated by the wavy line and is selectedfrom the group consisting of ##STR9## and acyloxy, R'_(a) and R"_(a) arealkyl of 1 to 4 carbon atoms or taken together with the nitrogen atomform a heterocycle of 5 to 6 chain members optionally containing anotherheteroatom with the proviso that when A and B are ##STR10## wherein R'and R" are both hydrogen, R₁ contains at least one nitrogen, phosphorusor silicium atom and when A and B are ##STR11##

R₁ is not a linear alkyl and their non-toxic, pharmaceuticallyacceptable acid addition salts.

R₁ is preferably an optionally unsaturated alkyl of 1 to 12 carbon atomssuch as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert.-butyl,n-pentyl, n-hexyl, 2-methyl-pentyl, 2,3-dimethyl-pentyl, n-heptyl,2-methyl-hexyl-, 2,2-dimethyl-pentyl, 3,3-dimethyl-pentyl,3-ethyl-pentyl, n-octyl, 2,2-dimethyl-hexyl, 3,3-dimethyl-hexyl,3-methyl-3-ethyl-pentyl, nonyl, 2,4-dimethylheptyl, n-decyl, vinyl,isopropenyl, allyl, 2-methyl-allyl and isobutenyl.

Examples of suitable optional substituents are thioalkyl such asthiomethyl or thioethyl and R₁ may be substituted with at least onehalogen such as fluorine, chlorine, bromine, iodine; substituted aminosuch as dimethylamino, R₁ may also be aryl or aralkyl, especially phenylor benzyl and the aromatic rings may be substituted in the p-, o- or m-positions with at least one member of the group consisting of alkyl of 1to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert.-butoxy;alkenyloxy of 2 to 4 carbon atoms such as allyloxy or vinyloxy; halogensuch as chlorine or fluorine; --OH; --CF₃ ; alkylthio of 1 to 4 carbonatoms such as methylthio or ethylthio which may be oxidized to sulfoxideor sulfone or a combination thereof such as3-fluoro-4-dimethylamino-phenyl.

R₁ may also be an aryl heterocycle optionally substituted such asthienyl, furyl, isothienyl, isofuryl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, pyridinyl, piperidinyl and other heterocyclesknown to there skilled in the art.

R₁ may also be cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl; cycloalkenyl such as cyclobutenyl or cycnopropenyl; arylsubstituted with a member of the group consisting of amino optionallysubstituted with one or 2 alkyls of 1 to 8 carbon atoms, nitrogenheterocycle group optionally containing a second oxygen, sulfur ornitrogen heteroatom such as morpholino or piperidinyl, substitutedaminoalkyl or alkoxy such as dimethylaminomethyl, dimethylaminoethyl ordimethylaminoethoxy or a silicum group such as trimethylsilylphenyl. Thepreferred aryl is phenyl and the substituent may also be a nitrogen atomwhich can be oxidized. The preferred heteroatom of R₁ is sulfur ornitrogen.

R₂ is preferably substituted alkyl of 1 to 4 carbon atoms such asmethyl, ethyl, propyl, isopropyl or butyl and preferably methyl or ethyland most preferably methyl. X is preferably an optionally substitutedpentagonal ring and R' and R" are alkyl as discussed above. When Re is asubstituted alkyl, it is preferably substituted with a dialkylamino suchas dimethylamino, diethylamino or methyl ethylamino. When R is ##STR12##it is preferably an dialkylamino such as dimethylamino, diethylamino ofmethylethylamino, it also is pyrrolidino, piperidino or morpholino.

R_(a) may also be alkanoyloxy such as acetyloxy, propionyloxy and theirhigher homologs or arylcarbonyloxy such as benzoyloxy.

Examples of suitable acids for the preparation of the non-toxic,pharmaceutically acceptable acid addition salts as are mineral acidssuch as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acidand phosphoric acid and organic acids such as formic acid, acetic acid,propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid,tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid,alkane sulfonic acids such as methane sulfonic acid and ethane sulfonicacid, arylsulfonic acids such as benzene sulfonic acid and p-toluenesulfonic acid and arylcarboxylic acids.

Among the preferred compounds of formula I are those wherein X is a ringof the formula ##STR13## wherein R₂ has the above definition, the dottedline in the 16,17-position indicates an optional double bond, Y is##STR14##

n is 1 or 2, R₅ is selected from the group consisting of hydrogen, alkylof 1 to 8 carbon atoms, alkenyl and alkynyl of 2 to 8 carbon atoms, arylof 6 to 14 carbon atoms and aralkyl of 7 to 15 carbon atoms, R₆ isselected from the group consisting of hydrogen, --OH, alkyl of 1 to 8carbon atoms, alkenyl and alkynyl of 2 to 8 carbon atoms, aryl of 6 to14 carbon atoms and aralkyl of 7 to 15 carbon atoms and R₃ and R₄ areindividually selected from the group consisting of hydrogen, --OH,--OAlK₄, ##STR15## alkenyl and alkynyl of 2 to 8 carbon atoms, ##STR16##or R₃ and R₄ together with the carbon atoms are ##STR17## or AlK₄, AlK₅and AlK₈ are selected from the group consisting of alkyl of 1 to 8carbon atoms and aralkyl of 7 to 15 carbon atoms, Alk₆ are selected fromthe group consisting of alkyl of 1 to 8 carbon atoms optionallysubstituted and aralkyl of 7 to 15 carbon atoms, alk₇ and Z₂ are alkylof 1 to 8 carbon atoms and Z₁ is selected from the group consisting ofhydrogen, alkyl of 1 to 8 carbon atoms and acyl of 1 to 8 carbon atoms.

Examples of preferred examples of R₅ or R₆ are methyl, ethyl, vinyl,isopropenyl, allyl, ethynyl, propynyl, phenyl and benzyl. Preferredexamples of R₃ and R₄ are --OAlK₄ and ##STR18## wherein AlK₄ and AlK₅are methyl, ethyl, n-propyl, butyl, pentyl, hexyl or benzyl or arevinyl, isopropenyl, allyl, 2-methylallyl, --C.tbd.CH, --C.tbd.CAlK₉wherein AlK₉ is methyl, ethyl, n-propyl, isopropyl, isopropenyl, butyl,benzyl or CF₃ -AlK₆, AlK₇ and AlK₈ have the same preferred values asAlK₄ and AlK₅. The preferred compounds are those in which R₃ and R₄ aredifferent except if one is hydrogen.

Among preferred values of ##STR19## are the groups ##STR20## wherein Z₁is hydrogen, alkyl of 1 to 8 carbon atoms or acyl of 2 to 8 carbon atomssuch as acetyloxy or benzoyl and Z₂ is alkyl of 1 to 8 carbon atoms suchas methyl. More preferable is the group ##STR21##

The D ring of the compounds of formula I is preferably not unsaturated,n is 1 and R₅ and R₆ are hydrogen. Another preferred group of "compoundsare those of formula I wherein R₃ is --OH or ##STR22## and R₄ is alkenylor alkynyl of 2 to 4 carbon atoms.

Among the preferred compounds of formula I are those wherein R₁ is ahydrocarbon of 1 to 18 carbon atoms containing at least one nitrogenatom and especially primary, secondary or tertiary alkyl of 1 to 8carbon atoms containing at least one heteroatom selected from the groupconsisting of oxygen, nitrogen and sulfur, at least one being nitrogenor substituted with a heterocycle containing at least one nitrogen atom.The hydrocarbon may be alkyl such as methyl, ethyl n-propyl, isopropyl,butyl, isobutyl, tert.-butyl, pentyl, hexyl or cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The heterocyclecontaining at least one nitrogen is preferably 2-pyridyl, 3-pyridyl,4-pyridyl, thiazolyl or piperidinyl.

Another preferred groups of compounds of the invention are those whereinR₁ is a heterocycle containing at least onenitrogen atom optionallysubsituted with alkyl of 1 to 8 carbon atoms such as 2-pyridyl,3-pyridyl, 4-pyridyl, thiazolyl or piperidinyl and the alkyl substituentis preferably methyl, ethyl or n-propyl.

R₁ may also preferably be aryl or aralkyl carrying amino of the formula##STR23## wherein R₇ and R₈ are alkyl of 1 to 8 carbon atoms or primary,secondary or tertiary alkyl of 1 to 8 carbon atoms containing at leastone heteroatom of the group consisting of --O--, --S-- or --N-- with atleast one being nitrogen or substituted with a heterocycle containing atleast one nitrogen atom. The alkyl, aryl, aralkyl and heterocycles arethose discussed above.

Especially preferred are compounds of formula I wherein R₁ is selectedfrom the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR24##Another preferred group of compounds of formula I are those wherein R₁is selected from the group consisting of thienyl, furyl, cycloalkyl of 3to 6 carbon atoms and phenyl optionally substituted with at least onemember of the group consisting of --OH, halogen, --CF₃, alkyl and alkoxyof 1 to 8 carbon atoms and alkylthio of 1 to 8 carbon atoms optionallyoxidized to sulfixide or sulfone and A and B rings are not ##STR25## Thepreferred substituents are those listed above and among the morepreferred values of R₁ are phenyl substituted with a member of the groupconsisting of chlorine, fluorine, methylthio, methylsulfonyl, methoxy,--OH and allyloxy.

Equally preferred compounds of formula I are those wherein the A and Brings are selected from the group consisting of ##STR26## wherein Ra ismorpholino or acetyloxy and R' and R" are both methyl or both --CN orone is hydrogen and the other is methyl or --CN, or R' and R" are bothhydrogen. Specific preferred compounds of formula I are2,2-dimethyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one,2,2-dicyano-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3 one,2α-methyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3 one, 2β-methyl-11β-(4-dimethylaminophenyl)17β-(prop-1-ynyl)-Δ⁴,9 -estradiene-17β-ol-3-one, 2-cyano-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one, 11β-(4-dimethylamino)-17α-(prop-1-ynyl)-Δ¹,3,5(10)-estratriene-3,17β-diol, 11β-(4-dimethylaminophenyl)17β-acetoxy-17α-(prop-1-ynyl)-Δ¹,3,5( 10)-estratriene-3-ol,3-methoxy-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ¹,3,5(10)-estratriene-17β-ol-,3-methoxy-11β-(4-dimethylaminophenyl)-17β-acetoxy-17α-(prop-1-ynyl)-Δ¹,3,5(10)-estratiene, 11β-( 3-methoxyphenyl)-17α-prop-1-ynyl)-Δ⁵(10)-estrene-17β-ol-3-ne,(e)11β-(3-methoxyphenyl)-17α-(prop-1-eny)-Δ⁵(10)-estrene-17β01-3-one,11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁵(10),estrene-17β-01-3-one,2-(acetyloxymethylene)-11β-(4-dimethyl-aminophenyl)-17α(prop-.sup.4,9-estradiene-17β-ol-3-one,2-(4-morpholinomethylene)-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one,11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-isoxazole[4,5-b].DELTA.⁴,9-estradiene-17β-ol, 11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10)-estratriene-3,17β-diol,11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10) -estradiene-17β-ol,3-(2-dimethylaminoethoxy)-11β-phenyl-66 ¹,3,5(10) -estratriene-17β-ol,11β-(4-pyridyl)-17α-(prop-1-ynyl-Δ⁴,9 -estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one,11β-4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-.DELTA.⁴,9,23cholatriene-20-yn-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]21-chloro-19-nor-17α-Δ.sup.4,9-pregnadiene-20-yne-17β-ol-3-one, N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17α-ol-3-one, N-oxide of 9α,10α-epoxy-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴-pregnene-20-yne-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one, 11β-[4-(N,N-dimethylamino)phenyl]-17α-(prop-2-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9 -estradiene17β-ol-3-one, N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-enyl)-Δ.sup.4,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one, γ-lactone of11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ¹,3,5(10)-pregnatriene-3,17β-diol-21-carboxylic acid, γ-lactone of3-methoxy-11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ¹,3,5(10)-pregnatriene-17β-ol-21-carboxylic acid, γ-lactone of11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁵(10)-pregnene-17β-ol-3-one-21-carboxylic acid, γ-lactone of 2α-methyl11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁴,9-pregnadiene-17β-ol-3-one-21-carboxylic acid, γ-lactone of 2β-methyl11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁴,9-pregnadiene-17β-ol-3-one-21-carboxylic acid, γ-lactone of 2,2-dimethyl11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁴,9-pregnadiene-17β-ol-3-one-21-carboxylic acid, γ-lactone of11β-[4-(N,N-methyl N-ethyl) amino-phenyl]-19-nor-17α-Δ⁵(10)-pregnadiene-17β-ol-3-one-21-carboxylic acid, and their non-toxic,pharmaceutically acceptable acid addition salts.

The novel process of the invention for the preparation of the compoundsof the formula ##STR27## wherein R₁, R₂ and X have the above definitionand R'₁ and R"₁ are each alkyl or one is hydrogen and the other is alkylor each are --CN or one is alkyl and the other is --CN comprisesreacting a compound of the formula ##STR28## wherein R₁, R₂ and X havethe above definitions after optionally reacting the same with aprotective agent for functional groups with a strong base and/or analkyl halide or tosyl or with an alkyl halide and then tosyl cyanidefollowed by removal of any protective groups, if necessary.

The process for the preparation of compounds of the formula ##STR29##corresponding to the formula comprises reacting a compound of formula IIwith a reducing agent to obtain a compound of the formula ##STR30## andreacting the latter with an aromatization acid agent to obtain thecompound of formula I_(B).

The process for the preparation of compounds of the formula ##STR31##wherein Re, R₁, R₂ and X have the above definitions comprises reacting acompound of formula II with an aromatization agent which is thensaponified and optionally reacted with an alkylation agent or anacylation agent.

The process for the preparation of a compound of the formula ##STR32##wherein R₁, R₂ and X have the above definitions comprises reacting acompound of formula II with a reducing agent.

The process for the preparation of a compound of the formula ##STR33##wherein Ra, R₁, R₂ and X have the above definitions comprises reacting acompound of formula II with a formylation agent to obtain a compound ofthe formula ##STR34## and reacting the latter with an acylation agent oran amine of the formula ##STR35## wherein R'_(a) and R"_(a) have theabove definitions.

The process for the preparation of a compound of the formula ##STR36##wherein R₁, R₂ and X have the above definitions comprises reacting acompound of formula III with hydroxyamine.

The process for the preparation of a compound of the formula ##STR37##wherein R₁, R₂ and X have the above definitions and R_(f) is hydrogen oralkyl comprises reacting a compound of formula I_(E) with a base toobtain the compound of formula I'_(A) wherein R_(f) is hydrogen and ifdesired, reacting the latter with a strong base and an alkyl halide toobtain the compound of formula I'_(A) wherein R_(f) is alkyl.

When the compounds of formula II contain one or more groups capable ofreacting with a reactant such as an alkyl halide, the groups preferablyare protected with a group known in the literature. This is particularlyimportant when the group ##STR38## contains a 17β-ol and this group ispreferably protected by tetrahydropyranyl by reacting the compound offormula II with dihydropyran.

The strong bases used are preferably alkali metal alcoholates such aspotassium tert.-butylatic but equally useful are alkali metal amidessuch as sodium amide or lithium amide prepared in situ. The alkylehalide is preferably an iodide such as methyl iodide and if gemdialkylation in the 2-positions is desired, at least two equivalents ofthe strong base are used and the reaction is effected in an excess ofalkyl iodide. Monoalkylation is obtained when only one equivalent of thestrong base is used. Generally, the α- and β-isomers may be separated byconventional techniques such as chromatography.

The addition of two cyano groups in the 2 -position is effected withtosyl cyanide whose preparation is described in Chem. Com., 1968, p. 440and is used as in Tetrahedron Letters No. 50 (1981), p. 5011. Theaddition of an alkyl halide and then tosyl cyanide yields the compoundswherein one of R'₁ and R"₁ is alkyl and the other is --CN and may beeffected under the preceding conditions.

The eventual removal of the protective groups may be effected by theclassical methods for instance, acid hydrolysis, preferably hydrochloricacid may be used to remove the tetrahydropyranyl group.

The reducing agent to prepare the compound of formula II₁ is preferablyan alkali metal borohydride such as sodium borohydride and the reactionis preferably effected in an alkanol such as methanol or ethanol. Thearomatization agent for the preparation of compounds of formulaI_(B).sbsb.1 is preferably a mineral acid such as hydrochloric acid orsulfuric acid or an agent such as phosphorus pentachloride, phosphorustribromide or phosphorus oxychloride or an anhydride such as aceticanhydride or trifluoroacetic anhydride. The aromatization agent for thepreparation of compounds of formula I_(B).sbsb.2 is preferably an acylhalide such as acetyl bromide or acetic anhydride or a mixture thereof.

The preferred saponification agent is an alkali metal base such assodium hydroxide or potassium hydroxide, sodium amide, potassiumtert.-butylate or lithium acetylide in ethylenediamine. The reaction ispreferably effected in a lower alkanol such as methanol or ethanol.

Depending on the conditions used and for example if the compoundcontains a group such as ##STR39## with a reactive group like 17β-ol, apartial acetylation of this group will occur resulting in a 17 β-olproduct containing a variable percentage of 17β-acetyloxy product andthe two can be separated by the usual methods such as chromatography.When the starting compound of formula II contains a 17-one group in thepentagonal ring, it can be reduced with sodium borohydride for example.

The eventual alkylation can be effected by usual methods and thepreferred alkylating agent is an alkyl halide such as alkyl iodide or analkylsulfate, preferably methyl, sulfate. The acylation may also beeffected by known methods is usually effected with an acyl halide. Thereducing agent used to form the compounds of formula I_(C) arepreferably an alkali metal in liquid ammonia, preferably lithium butsodium is also useful.

Depending upon the amount of metal used, other portions of the moleculemay be effected and for example, this is the case when the compound hasthe group ##STR40## containing a 17α-acetylenic group such as propynyl.The use of two moles of alkali metal results in a practically selectivereduction of a 3-keto-Δ⁴,9 -steroid into a 3-keto-Δ⁵(10) -steroid. If asupplemental amount of reducing agent is used, there is simultaneouslyobtained a reduction of an acetylenic group into a trans olefin group,i.e. a 17-prop-1-ynyl into a 17α-prop-1-enyl. The separation of the twoproducts may be effected by classical methods such as chromatography.

The formylation of the compounds of formula II is effected under knownconditions such as by reaction with a formate such as alkyl formates,i.e. ethyl formate, in the presence of a strong base such as sodiumhydride and the acylation of the compound of formula III is effectedunder known conditions as well. Preferably, the acylating agent is anacid anhydride or acid halide such as acetyl chloride and the reactionis effected in the presence of an acid receptor such as pyridine.

The reaction with an amine of the formula ##STR41## is effected underknown conditions, preferably with heat. The reaction of the compound offormula III with hydroxylamine which is preferably in the form of anacid salt such as its hydrochloride is effected in a refluxing alkanolsuch as tert.-butanol. The hydrolysis of the compounds of formula I_(E)is preferably effected with a base such as sodium hydroxide or potassiumhydroxide, preferably in methanol. The alkylation of the compounds offormula I'_(A) when R_(f) is hydrogen is effected under the usualconditions indicated above.

In a preferred mode of the process of the invention, the startingmaterials of formula II have the group ##STR42## which is ##STR43##wherein R₂ is methyl, R₃ is --OH or ##STR44## and AlK₉ is alkyl of 1 to4 carbon atoms, R₄ is alkenyl or alkynyl of 2 to 4 carbon atoms and R₁is ##STR45## or alkoxyphenyl wherein the alkyl has 1 to 4 carbon atomsand AlK₁₁ and AlK₁₂ are alkyl of 1 to 4 carbon atoms.

The novel process of the invention for the preparation of compounds offormula II comprises reacting a compound of the formula ##STR46##wherein K is a ketone blocked in the form of a ketal, thioketal, oximeor methyloxime and R₁, R₂ and X have the above definitions with adehydration agent capable of freeing the ketone group to form a compoundof the formula ##STR47##

The process of the invention is particularly useful for forming productsof formula I' wherein X form a pentagonal ring of the formula ##STR48##wherein R₂, R₃, R₄, Y and the dotted line in the 16,17-position have theabove definition.

In a preferred mode of the process of the invention, the dehydrationagent capable of freeing the ketone group is a sulfonic acid resin inthe acid form such as a commercial sulfonic acid resin based onpolystyrene or a styrene-divinylbenzene polymer but equally useful areinorganic acids such as sulfuric acid or hydrochloric acid in a loweralkanol or perchloric acid in acetic acid or a sulfonic acid such asp-toluene sulfonic acid.

It goes without saying that when one of R₃ or R₄ in the compounds offormula II obtained above is --OH, the compounds of formula II may bereacted with an etherification agent or an esterification agent which isone of those discussed above. When R₃ or R₄ is a 17-acyloxy, thecompound may be optionally saponified with a saponification agent suchas a base like sodium hydroxide, potassium hydroxide, potassium amide orpotassium tert.-butylate and the reaction is preferably effected in alower alkanol such as ethanol or methanol but equally useful is lithiumacetylide in ethylenediamine.

Another object of the invention is a process for the preparation of thecompounds of formula B wherein a compound of the formula ##STR49## isreacted with a compound selected from the group consisting of LiCu(R₁)₂, LiR₁ and R₁ Mg Hal wherein R₁ has the above definition and Hal ishalogen in the presence of a cuprous halide. In a preferred mode of thesaid process, the reaction is effected at room temperature and thereactant is R₁ Mg Hal in the presence of a cuprous salt.

Another object of the invention is a process for the preparation of acompound of the formula ##STR50## wherein R₁, R₂ and K have the abovedefinitions, R'₃ is selected from the group consisting of --OH andOR_(c), R_(c) is the residue AlK₄ of an ether group or COAlK₅ of anester group and R'₄ is hydrogen or alkenyl or alkynyl of 2 to 8 carbonatoms comprising reacting a compound of the formula ##STR51## with acompound selected from the group consisting of LiCu(R₁)₂, R₁ Li and R₁Mg Hal in the presence of a cuprous halide to obtain a compound of theformula ##STR52## and either reducing the latter to obtain thecorresponding 17-ol compound or with an appropriate magnesium to obtainthe corresponding 17α-substituted-17β-ol steroid or with anorganometallic derivative such as a lithium or potassium derivative toobtain the corresponding 17α-substituted-17β-ol steroid or with acyanuration agent to obtain the corresponding 17α-ol-17β-cyano steroid,protecting the hydroxy group and reacting the latter with anorganometallic compound as discussed above to obtain the corresponding17α-substituted-[17β-ol steroid and in the case of one of the compoundsobtained is 17-hydroxylated, reacting it with an etherification agent oresterification agent and in the case when one of the compounds containsa 17 substituent with a triple bond reacting the latter with a reducingagent to obtain the corresponding ethylenic derivative.

In a preferred mode of the latter process, the reaction of the compoundof formula A' with a compound of the group consisting of R₁ Li,LiCu(R₁)₂ or R₁ Mg Hal is effected under the previously describedconditions. The different reactants for reaction with the compounds offormula B" are known in steroid chemistry and are illustrated in thespecific examples.

The novel intermediates of the invention are the compounds of formula Band B". Particularly preferred compounds of the invention are3,3-[1,2-ethanediylbisoxy]-11β-[4-trimethylsilyl-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-(4-pyridyl)-17α-(prop-1-ynyl)-.DELTA.⁹-estrene-5α,17β-diol,3,3-(1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-propyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N,-dimethylaminoethoxy)phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol and3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-ynyl)-Δ⁹ -estrene-5α,17β-diol.

The novel antiglucocorticoid compositions of the invention are comprisedof an antiglucocorticoidally effective amount of at least one compoundof formula I and its non-toxic, pharmaceutically acceptable acidaddition salts and an inert pharmaceutical carrier. The compositions maybe in the form of tablets, dragees, gelules, granules, suppositories,ovules, injetable solutions or suspensions, pommades, creams and gelsprepared in the usual fashion.

Examples of suitable excipients are talc, arabic gum, lactose, starch,magnesium stearate, cacao butter, aqueous and non-aqueous vehicles,fatty bodies of animal or vegetable origin, paraffinic derivatives,glycols, diverse wetting agents, dispersants and emulsifiers andpreservatives.

The compositions are useful to principally counter effect secondaryeffects of glucocorticoids and are useful for the treatment of troublesdue to a hypersecretion of glucocorticoids, especially against aging ingeneral and especially against hypertension, atherosclerosis,osteoporosis, diabetics, obesity as well as immuno-suppressive effectsand insomnia

The study of the products on hormonal receptors shows that they possessprogestomimetic or antiprogestomimetic activity or androgen orantiandrogen activity. The compounds of formula I which possessantiprogestomimetic activity are useful as original contraceptives or asinterruption of pregnancy agents. They may also be useful for inducingregular cycles in females and more generally in warm-blooded females.

The products may be administered during periods or when progesteronedischarges an essential physiological role which is notably during theluteal phase of the cycle at the moment of nidation or implantation ofthe embryo and during the pregnancy. One method of contraception of theinvention consists of administering to the female at least one of theproducts of formula I or its salts 1 to 5 days before the end of thecycle. The products are preferably administered orally or in the vaginabut may also be administered parenterally or endonasally.

The compounds of formula I possessing antiprogestomimetic activity areequally useful against hormonal irregularities and by other means theypresent an interest in the treatment of hormonodependent tumors. Theiraction against hypophysial secretions make the compounds useful inmenopause.

The compounds are equally useful for the synchronization of estrus inlarger animals such as bovines and sheep and are useful for controllingthe fertility of household pets such as cats and dogs.

Certain compounds of formula I also present progestomimetic propertiesand are useful for the treatment of amenorrhea, of dysmenorrhea andluteal insufficiencies.

The compounds of formula I possessing antiandrogenic activity are usefulin the treatment of hypertrophies and prostate cancer, ofhyperandrogenia, of anemia, hirsutism and of acne as well as malecontraception.

Certain of the compounds of formula I possess estrogenic properties andare useful for the treatment of troubles due to a hypofolliculinia suchas amenorrhea, dysmenorrhea, repeated abortions, premenstrual troublesas well as for the treatment of menopause.

Certain of the compounds of formula I possess antiestrogenic propertiesand are useful for the treatment of mammalogy carcinoma and its metastases.

Among the preferred compositions of the invention are those wherein theactive ingredient is selected from the group consisting of2,2-dimethyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3 -one,2,2-dicyano-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one,2α-methyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one,2β-methyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one,2-cyano-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one, 11β-(4-dimethylamino)-17α-(prop-1-ynyl)-Δ¹,3,5(10) -estratriene-3,17β-diol,11β-(4-dimethylaminophenyl)-17β-acetoxy-17α-(prop-1-ynyl)-Δ¹,3,5(10)-estratriene-3-ol,3-methoxy-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ¹,3,5(10)-estratriene-17β-ol,3-methoxy-11β-(4-dimethylaminophenyl)-17.beta.-acetoxy-17α-(prop-1-ynyl)-Δ¹,3,5(10)-estratriene, 11β-(3-methoxyphenyl)-17α-(prop-1-ynyl)-Δ⁵(10)-estrene-17β-ol-3-one, (E)11β-(3-methoxyphenyl)-17α-(prop-1-enyl)-Δ⁵(10) -estrene-17β-ol-3-one,11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁵(10)-estrene-17β-ol-3-one,2-(acetyloxymethylene)-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one,2-(4-morpholinomethylene)-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one,11β-(4-dimethylaminophenyl)-17-(prop-1-ynyl)-isoxazolo[4,5-b]-Δ⁴,9-estradiene-17β-ol, 11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10)-estratriene-3,17β-diol,11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10) -estratriene-17β-ol,3-(2-dimethylaminoethoxy)-11β-phenyl-Δ¹,3,5(10) -estratriene-17β-ol11β-(4-pyridyl)-17α-(prop-1-ynyl-Δ⁴,9 -estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylaminoethoxy)-phenyl-]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-.DELTA.⁴,9,23cholatriene-20-yn-17β-ol-3-one,11β-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ.sup.4,9-pregnadiene-20-yne-17β-ol-3-one, N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19nor-17α-Δ.sup.4,9-pregnadiene-20-yne-17β-ol-3-one, N-oxide of 9α,10α-epoxy-11-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17.alpha.-Δ⁴-pregnene-20-yne-17β-ol-3 -one,11β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9 -estradiene17β-ol-3-one, N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one,11β-[-4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-enyl)-2-enyl(-.DELTA.⁴,9-estradiene-17β-ol-3-one,11β-[4-N,N-dimethylaminoethylthio)-phenyl]-17α-prop-1-ynyl-.DELTA.⁴,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one, γ-lactone of11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ¹,3,5(10)-pregnatriene-3,17β-diol-21-carboxylic acid, γ-lactone of3-methoxy-11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ¹,3,5(10)-pregnatriene-17β-ol-21-carboxylic acid, γ-lactone of11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁵(10)-pregnene-17β-ol-3-one-21-carboxylic acid, γ-lactone of 2α-methyl11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁴,9-pregnadiene-17β-ol-3-one-21-carboxylic acid, γ-lactone of 2β-methyl11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁴,9-pregnadiene-17β-ol-3-one-21-carboxylic acid, γ-lactone of 2,2-dimethyl11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁴,9-pregnadiene-17β-ol-3-one-21-carboxylic acid, γ-lactone of11β-[4-(N-methyl N-ethyl) amino-phenyl]-19-nor-17α-Δ⁵(10)-pregnene-17β-ol-3-one-21-carboxylic acid, and their non-toxic, pharmaceuticallyacceptable acid addition salts.

The novel method of the invention for inducing antiglucocorticoidactivity in warm-blooded animals, including humans, comprisesadministering to warm-blooded animals an antiglucocorticoidallyeffective amount of at least one compound of formula I and theirnon-toxic, pharmaceutically acceptable acid addition salts. Thecompounds may be administered orally, rectally, parenterally ortopically and the usual daily dose is 0,15 to 0,150 mg/kg depending uponthe compound, the condition treated and the method of treatment.

The antiprogestomimetic compostions of the invention contain aphysiologically active quantity of at least one product of formula I andits pharmaceutically acceptable acid addition salts asantiprogestomimetics.

These compositions may be administered via the digestive tract,parenterally or locally, particularly in the vagina or via the endonasalroute. They may be in the form of a simple tablet or lozenges, gelatincapsules, granulated, suppositories, ovules, injectable preparations,ointments, creams or gels which are prepared according to the usualmethods.

Excipients which may be employed are talc, gum arabic, lactose starch,magnesium stearate, cocoa butter, animal and vegetable fats, paraffinderivatives, glycols, various wetting agents, dispersants, emulsifiersand preservatives.

The antiprogestomimetic compositions of the invention have remarkableproperties as may be seen in the pharmacological tests which aredescribed later.

The antiprogestomimetic compositions of the invention are usedessentially to induce menses in female warm blooded animals.

The induction of menses during the luteal phase of the cycle andparticularly at the end of the luteal phase permits the use of thecompositions of the invention as contraceptives.

The antiprogrestomimetic compositions according to the invention may beequally used as agents to interrupt pregnancy since experiments withanimals have demonstrated them to be abortive at any period ofgestation.

The new method of the invention consists of inducing the menses in warmblooded female animals including women and is characterised in that oneadministers a quantity of antiprogestomimetic compound which isphysiologically active such as a product of formula I.

But it is understood that the essential role of progesterone is assignedduring the luteal phase of the cycle at the moment of implantation ofthe embryo and during pregnancy.

The use of an antiprogestomimetic as an inducer of menstruation has beenproposed, for example, in the tenth World Health Organization reportpage 80 and later in Chemtech, September 1977 page 566.

The method of utilization of this product is equally suggested as"post-coital and once-a-month drugs" in the report in WHO and in theexpression "when taken monthly . . . will induce menstruation" in theChemtech article.

Meanwhile before the products of formula I, no product having therequired pharmacological properties for such a utilization had beensynthesized.

The method of contraception according to the invention consists ofadministering to the woman about 10 mg to 1 gram of the product for 1 to5 days preferably at the end of the menstrual cycle. Preferably onetakes about 25 to 200 mg of the product per day.

Preferably the product is administered orally. Administration of theproduct via the vagina is equally suitable.

The method of using the products of the invention to interrupt pregnancyconsists in administering to warm blooded females at least aphysiolgically active amount of the product of formula I.

One administers an amount on the order of about 50 mg to 1 gram per dayof the product for 1 to 5 days toward the end of the menstrual cycle.Preferably 200 mg to about 500 mg is used in women.

The preferred manner of administration of this product is orally or viathe vagina.

The products of formula I can be used in synchronizing the fertileperiods of animals particularly cattle and sheep. They can also be usedto control the fertility of pets like dogs or cats.

Finally, the products of formula I , which have anti-androgen activitycan be used for human contraception.

The compounds of formula A and especially of formula A' used to preparethe compounds of formula B or B" are generally known compounds which canbe prepared by reacting the corresponding Δ⁵(10),9(11) steroids with anepoxidation agent selective for the 5(10) double bond, for example withhydrogen peroxide in the presence of hexachloroacetone orhexafluoroacetone as described in French patent No. 2,423,486. The newcompound,3,3-[1,2-ethanediyl-bisoxy]-17α-(prop-1-ynyl]-5α,10α-epoxy-Δ⁹(11)-estrene-17β-ol is prepared in the Example.

    __________________________________________________________________________     ##STR53##        R.sub.1            R.sub.2                                                                             R.sub.3  R.sub.4                   __________________________________________________________________________     ##STR54##                                                                                      ##STR55##         CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CCSiMe.sub.3               "                "                  "     CCH      OH                         "                "                  "     CCSiMe.sub.3                                                                           OH                         "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     OH       CCCH.sub.3                 "                "                  "     OH       CH.sub.2CCH                "                "                  CH.sub.3                                                                             ##STR56##                                                                             H                          "                "                  "     "        OH                                           ##STR57##         "     OH       CCH                        "                "                  "                                                                                    ##STR58##                          "                "                  "     C CH     OH                         "                "                  "     OH       CH.sub.2CCH                "                                                                                               ##STR59##         "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR60##         "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2C CH               "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     CCH      OH                         "                "                  "     CCSiMe.sub.3                                                                           OH                          ##STR61##                                                                                      ##STR62##         CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "         CCCH.sub.2 CH.sub.3       "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CCSiMe.sub.3               "                "                  "     CCH      OH                         "                "                  "     CCSiMe.sub.3                                                                           OH                         "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     OH       CCCH.sub.3                 "                "                  "     OH       CH.sub.2CCH                "                "                  CH.sub.3                                                                             ##STR63##                                                                             H                          "                "                  "     "        OH                         "                                                                                               ##STR64##         "     OH       CCH                        "                "                  "                                                                                    ##STR65##                          "                "                  "     CCH      OH                         "                "                  "     OH       CH.sub.2CCH                "                                                                                               ##STR66##         "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR67##         "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     CCH      OH                         "                "                  "     C CSiMe.sub.3                                                                          OH                          ##STR68##                                                                                      ##STR69##         CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CCSiMe.sub.3               "                "                  "     CCH      OH                         "                "                  "     CCSiMe.sub.3                                                                           OH                         "                "                  CH.sub.2 CH.sub.3                                                                   OH       C CH                       "                "                  "     OH       CCCH.sub.3                 "                "                  "     OH       CH.sub.2CCH                "                "                  CH.sub.3                                                                             ##STR70##                                                                             H                          "                "                  "     "        OH                         "                                                                                               ##STR71##         "     OH       CCH                        "                "                  "                                                                                    ##STR72##                          "                "                  "     CCH      OH                         "                "                  "     OH       CH.sub.2C CH               "                                                                                               ##STR73##         "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR74##         "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        C CCH.sub.2 CH.sub.3       "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     CCH      OH                         "                "                  "     CCSiMe.sub.3                                                                           OH                          ##STR75##                                                                                      ##STR76##         CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "         CH.sub.2CCH               "                "                  "     "        CCSiMe.sub.3               "                "                  "     CCH      OH                         "                "                  "     CCSiMe.sub.3                                                                           OH                         "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     OH       CCCH.sub.3                 "                "                  "     OH       CH.sub.2CCH                "                "                  CH.sub.3                                                                             ##STR77##                                                                             H                          "                "                  "     "        OH                         "                                                                                               ##STR78##         "     OH       C CH                       "                "                  "                                                                                    ##STR79##                          "                "                  "     CCH      OH                         "                "                  "     OH       CH.sub.2CCH                "                                                                                               ##STR80##         "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR81##         "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     CCH      OH                         "                "                  "     CCSiMe.sub.3                                                                           OH                          ##STR82##                                                                                      ##STR83##         CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  CH.sub.3                                                                             ##STR84##                                                                             H                          "                "                  "     "        OH                         "                "                  "                                                                                    ##STR85##                                                                             H                           ##STR86##                                                                                      ##STR87##         "     OH       CCH                        "                "                  "                                                                                    ##STR88##                          "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR89##                                                                             H                          "                                                                                               ##STR90##         "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "         CH.sub.2CCH               "                "                  "     CCH      OH                          ##STR91##                                                                                      ##STR92##         "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCl                        "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CCSiMe.sub.3               "                "                  "                                                                                    ##STR93##                                                                             H                           ##STR94##                                                                                      ##STR95##         CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  CH.sub.3                                                                             ##STR96##                                                                             H                          "                "                  "     "        OH                         "                "                  "                                                                                    ##STR97##                                                                             H                           ##STR98##                                                                                      ##STR99##         "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR100##                                                                            H                          "                "                  "                                                                                    ##STR101##                          ##STR102##      "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                          ##STR103##                                                                                     ##STR104##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CCSiMe.sub.3               "                "                  "                                                                                    ##STR105##                                                                            H                           ##STR106##                                                                                     ##STR107##        CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2C CH               "                "                  CH.sub.3                                                                             ##STR108##                                                                            H                          "                "                  "     "        OH                         "                "                  "                                                                                    ##STR109##                                                                            H                           ##STR110##                                                                                     ##STR111##        "     OH       CCH                        "                "                  "                                                                                    ##STR112##                         "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR113##                                                                            H                          "                                                                                               ##STR114##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                          ##STR115##                                                                                     ##STR116##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CCSiMe.sub.3               "                "                  "                                                                                    ##STR117##                                                                            H                           ##STR118##                                                                                     ##STR119##        CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  CH.sub.3                                                                             ##STR120##                                                                            H                          "                "                  "     "        OH                         "                "                  "                                                                                    ##STR121##                                                                            H                           ##STR122##      "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        C CCH.sub.2 CH.sub.3       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR123##                                                                            H                          "                                                                                               ##STR124##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     C CH     OH                          ##STR125##                                                                                     ##STR126##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CCSiMe.sub.3               "                "                  "                                                                                    ##STR127##                                                                            H                           ##STR128##                                                                                     ##STR129##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR130##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR131##        "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCF.sub.3                 "                "                  "     CCSiMe.sub.3                                                                           OH                         "                "                  "                                                                                    ##STR132##                                                                            H                          "                "                  "     "        OH                         "                "                  "                                                                                    ##STR133##                                                                            H                          "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                "                "                  "                                                                                    ##STR134##                                                                            H                          "                                                                                               ##STR135##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR136##                                                                            H                          "                "                  "     OH       CH.sub.2CCH                "                                                                                               ##STR137##        "     "        "                           ##STR138##                                                                                     ##STR139##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR140##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR141##        "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCF.sub.3                 "                "                  "     CCSiMe.sub.3                                                                           OH                         "                "                  "                                                                                    ##STR142##                                                                            H                          "                "                  "     "        OH                         "                "                  "                                                                                    ##STR143##                                                                            H                          "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                "                "                  "                                                                                    ##STR144##                                                                            H                          "                                                                                               ##STR145##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR146##                                                                            H                          "                "                  "     OH       CH.sub.2CCH                "                                                                                               ##STR147##        "     "        "                           ##STR148##                                                                                     ##STR149##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR150##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR151##        "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCF.sub.3                 "                "                  "     CCSiMe.sub.3                                                                           OH                         "                "                  "                                                                                    ##STR152##                                                                            H                          "                "                  "     "        OH                         "                "                  "                                                                                    ##STR153##                                                                            H                          "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2CH.sub. 3        "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                "                "                  "                                                                                    ##STR154##                                                                            H                          "                                                                                               ##STR155##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR156##                                                                            H                          "                "                  "     OH       CH.sub.2CCH                "                                                                                               ##STR157##        "     "        "                           ##STR158##                                                                                     ##STR159##        CH.sub.3                                                                            OH       C CH                       "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR160##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR161##        "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCF.sub.3                 "                "                  "     CCSiMe.sub.3                                                                           OH                         "                "                  "                                                                                    ##STR162##                                                                            H                          "                "                  "     "        OH                         "                "                  "                                                                                    ##STR163##                                                                            H                          "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        C CSiMe.sub.3              "                "                  "     "        CH.sub.2CCH                "                "                  "                                                                                    ##STR164##                                                                            H                          "                                                                                               ##STR165##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR166##                                                                            H                          "                "                  "     OH       CH.sub.2CCH                "                                                                                               ##STR167##        "     "        "                           ##STR168##                                                                                     ##STR169##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR170##                                                                            H                           ##STR171##                                                                                     ##STR172##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CH.sub.2CCH                "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCH                        "                "                  "     "        CCSiMe.sub.3                ##STR173##      "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                          ##STR174##      "                  "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                 ##STR175##                                                                                     ##STR176##        "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        C CCH.sub.3                "                "                  "     "        CCCl                        ##STR177##                                                                                     ##STR178##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR179##                                                                            H                           ##STR180##                                                                                     ##STR181##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CH.sub.2CCH                "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCH                        "                "                  "     "        CCSiMe.sub.3                ##STR182##      "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2C CH               "                "                  "     CCH      OH                          ##STR183##      "                  "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                 ##STR184##                                                                                     ##STR185##        "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                   

    __________________________________________________________________________     ##STR186##                                                                                     ##STR187##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR188##                                                                            H                           ##STR189##                                                                                     ##STR190##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CH.sub.2CCH                "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCH                        "                "                  "     "        CCSiMe.sub.3                ##STR191##      "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                          ##STR192##      "                  "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                 ##STR193##                                                                                     ##STR194##        "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                        ##STR195##                                                                                     ##STR196##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR197##                                                                            H                           ##STR198##                                                                                     ##STR199##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CH.sub.2CCH                "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCH                        "                "                  "     "        CCSiMe.sub.3                ##STR200##      "                  "     OH       C CH                       "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                          ##STR201##      "                  "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        C CCH.sub.3                "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCCl                       "                "                  "     "        CCSiMe.sub.3               "                "                  "     "        CH.sub.2CCH                 ##STR202##                                                                                     ##STR203##        "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                        ##STR204##                                                                                     ##STR205##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     "        H                          "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR206##                                                                            H                                            ##STR207##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        C CCl                      "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR208##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        H                          "                                                                                               ##STR209##        "     "        CCH                        "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR210##                                                                            H                          "                                                                                               ##STR211##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub. 2CCH               "                                                                                               ##STR212##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR213##                                                                                     ##STR214##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     "        H                          "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR215##                                                                            H                          "                                                                                               ##STR216##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR217##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        C CCF.sub.3                "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        H                          "                                                                                               ##STR218##        "     "        CCH                        "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR219##                                                                            H                          "                                                                                               ##STR220##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR221##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR222##                                                                                     ##STR223##        CH.sub.3                                                                            OH       CH.sub.2C CH               "                "                  "     "        H                          "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR224##                                                                            H                          "                                                                                               ##STR225##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR226##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        H                          "                                                                                               ##STR227##        "     "        CCH                        "                "                  "     "        CH.sub.2CCH                "                "                  "     C CH     OH                         "                "                  "                                                                                    ##STR228##                                                                            H                          "                                                                                               ##STR229##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR230##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR231##                                                                                     ##STR232##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     "        H                          "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR233##                                                                            H                          "                                                                                               ##STR234##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR235##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        H                          "                                                                                               ##STR236##        "     "        CCH                        "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR237##                                                                            H                          "                                                                                               ##STR238##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR239##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR240##                                                                                     ##STR241##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR242##                                                                            H                          "                                                                                               ##STR243##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCCF.sub.3                 "                "                  "     OH       CCH                        "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2                   "                "                  "                                                                                    ##STR244##                                                                            CH.sub.3                   "                "                  "     OH       CH.sub.2CN                  ##STR245##      "                  "     OH       CCH                        "                "                  "     "        C CCH.sub.3                "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR246##                                                                            H                           ##STR247##                                                                                     ##STR248##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                                 "                  CH.sub.2 CH.sub.3                                                                   "        CCH                        "                "                  "     "        CCCH.sub.3                  ##STR249##                                                                                     ##STR250##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR251##                                                                            H                          "                                                                                               ##STR252##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCCF.sub.3                 "                "                  "     OH       CCH                        "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2                   "                "                  "                                                                                    ##STR253##                                                                            CH.sub.3                   "                "                  "     OH       CH.sub. 2CN                 ##STR254##      "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR255##                                                                            H                           ##STR256##      "                  "     "        "                          "                "                  "      CCH     OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                                 "                  CH.sub.2 CH.sub.3                                                                   "        CCH                        "                "                  "     "        CCCH.sub.3                  ##STR257##                                                                                     ##STR258##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR259##                                                                            H                          "                                                                                               ##STR260##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCCF.sub.3                 "                "                  "     OH       CCH                        "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2                   "                "                  "                                                                                    ##STR261##                                                                            CH.sub.3                   "                "                  "     OH       CH.sub.2CN                  ##STR262##      "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR263##                                                                            H                           ##STR264##                                                                                     ##STR265##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                                 "                  CH.sub.2 CH.sub.3                                                                   "        C CH                       "                "                  "     "        CCCH.sub.3                  ##STR266##                                                                                     ##STR267##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR268##                                                                            H                          "                                                                                               ##STR269##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCCF.sub.3                 "                "                  "     OH       CCH                        "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2                   "                "                  "                                                                                    ##STR270##                                                                            CH.sub.3                   "                "                  "     OH       CH.sub.2CN                  ##STR271##      "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CC Cl                      "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR272##                                                                            H                           ##STR273##                                                                                     ##STR274##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCH.sub.2CH.sub.3         "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                                 "                  CH.sub.2 CH.sub.3                                                                   "        CCH                        "                "                  "     "        CCCH.sub.3                  ##STR275##                                                                                     ##STR276##        CH.sub.2 CH.sub.3                                                                   OH       CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "                                                                                    ##STR277##                                                                            CH.sub.3                   "                "                  "                                                                                    ##STR278##                                                                            H                          "                "                  "     CCH      OH                         "                                                                                               ##STR279##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR280##                                                                            H                          "                "                  "                                                                                    ##STR281##                                                                            CH.sub.3                   "                "                  "                                                                                    ##STR282##                                                                            H                          "                                                                                               ##STR283##        "     "        "                          "                "                  "     "        CH.sub.3                   "                "                  "                                                                                    ##STR284##                                                                            H                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                                                                                               ##STR285##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                 ##STR286##                                                                                     ##STR287##        CH.sub.2 CH.sub.3                                                                   OH       CH.sub.2CC H               "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "                                                                                    ##STR288##                                                                            CH.sub.3                   "                "                  "                                                                                    ##STR289##                                                                            H                          "                "                  "     CCH      OH                         "                                                                                               ##STR290##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2C CH               "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR291##                                                                            H                          "                "                  "                                                                                    ##STR292##                                                                            CH.sub.3                   "                "                  "                                                                                    ##STR293##                                                                            H                          "                                                                                               ##STR294##        "     "        "                          "                "                  "     "        CH.sub.3                   "                "                  "                                                                                    ##STR295##                                                                            H                          "                "                  "     CCH      OH                         "                "                  "     OH       C CH                       "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                                                                                               ##STR296##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                 ##STR297##                                                                                     ##STR298##        CH.sub.2 CH.sub.3                                                                   OH       CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "                                                                                    ##STR299##                                                                            CH.sub.3                   "                "                  "                                                                                    ##STR300##                                                                            H                          "                "                  "     CCH      OH                         "                                                                                               ##STR301##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        C CCl                      "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR302##                                                                            H                          "                "                  "                                                                                    ##STR303##                                                                            CH.sub.3                   "                "                  "                                                                                    ##STR304##                                                                            H                          "                                                                                               ##STR305##        "     "        "                          "                "                  "     "        CH.sub.3                   "                "                  "                                                                                    ##STR306##                                                                            H                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                                                                                               ##STR307##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                 ##STR308##                                                                                     ##STR309##        CH.sub.2 CH.sub.3                                                                   OH       CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "                                                                                    ##STR310##                                                                            CH.sub.3                   "                "                  "                                                                                    ##STR311##                                                                            H                          "                "                  "     CCH      OH                         "                                                                                               ##STR312##        CH.sub.3                                                                            OH       C CH                       "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR313##                                                                            H                          "                "                  "                                                                                    ##STR314##                                                                            CH.sub.3                   "                "                  "                                                                                    ##STR315##                                                                            H                          "                                                                                               ##STR316##        "     "        "                          "                "                  "     "        CH.sub.3                   "                "                  "                                                                                    ##STR317##                                                                            H                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub. 2CHCH.sub.2        "                                                                                               ##STR318##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH            

    __________________________________________________________________________     ##STR319##                                                                                     ##STR320##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR321##                                                                            H                                            ##STR322##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR323##                                                                            H                          "                                                                                               ##STR324##        "     OH       CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR325##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     C CH     OH                         "                "                  "                                                                                    ##STR326##                                                                            H                          "                                                                                               ##STR327##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                Me.sub.3 Si CH.sub.2                                                                             "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                          ##STR328##      "                  "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR329##                                                                                     ##STR330##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR331##                                                                            H                          "                                                                                               ##STR332##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR333##                                                                            H                          "                                                                                               ##STR334##        "     OH       CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR335##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR336##                                                                            H                          "                                                                                               ##STR337##        "     "        "                          "                "                  "     C CH     OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                Me.sub.3 Si CH.sub.2                                                                             "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                          ##STR338##      "                  "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCOH.sub.3                  ##STR339##                                                                                     ##STR340##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR341##                                                                            H                          "                                                                                               ##STR342##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR343##                                                                            H                          "                                                                                               ##STR344##        "     OH       CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR345##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        C CCl                      "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR346##                                                                            H                          "                                                                                               ##STR347##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub. 2CCH               "                Me.sub.3 Si CH.sub.2                                                                             "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                          ##STR348##      "                  "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR349##                                                                                     ##STR350##        CH.sub.3                                                                            CCH      OH                         "                "                  "                                                                                    ##STR351##                                                                            H                          "                                                                                               ##STR352##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR353##                                                                            H                          "                                                                                               ##STR354##        "     OH       CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                                                                                               ##STR355##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR356##                                                                            H                          "                                                                                               ##STR357##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                Me.sub.3 Si CH.sub.2                                                                             "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2C CH               "                "                  "     CCH      OH                          ##STR358##      "                  "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR359##      Me.sub.3 Si CH.sub.2                                                                             CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  CH.sub.2 CH.sub.3                                                                   CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub. 3                "                "                  "     "        CH.sub.2CCH                 ##STR360##                                                                                     ##STR361##        "     "        CCCH.sub.3                 "                "                  "                                                                                    ##STR362##                                                                            H                          "                                                                                               ##STR363##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub. 2        "                "                  "     "        CH.sub.2 CN                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR364##                                                                            H                          "                "                  "                                                                                    ##STR365##                                                                            CH.sub.3                   "                "                  "     OH       H                          "                                                                                               ##STR366##        "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2 CCH               "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR367##                                                                            H                          "                "                  "                                                                                    ##STR368##                                                                            CH.sub.3                   "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                 ##STR369##      Me.sub.3 Si CH.sub.2                                                                             CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  CH.sub.2 CH.sub.3                                                                   C CH     OH                         "                "                  "     OH       CCH                        "                "                  ""    CCCH.sub.3                          "                "                  "     "        CH.sub.2CCH                 ##STR370##                                                                                     ##STR371##        "     "        CCCH.sub.3                 "                "                  "                                                                                    ##STR372##                                                                            H                          "                                                                                               ##STR373##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        C CCH.sub.3                "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2 CN                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR374##                                                                            H                          "                "                  "                                                                                    ##STR375##                                                                            CH.sub.3                   "                "                  "     OH       H                          "                                                                                               ##STR376##        "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "         CCCH.sub.2 CH.sub.3       "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR377##                                                                            H                          "                "                  "                                                                                    ##STR378##                                                                            CH.sub.3                   "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                 ##STR379##      Me.sub.3 Si CH.sub.2                                                                             CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  CH.sub.2 CH.sub.3                                                                   CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                 ##STR380##                                                                                     ##STR381##        "     "        CCCH.sub.3                 "                "                  "                                                                                    ##STR382##                                                                            H                          "                                                                                               ##STR383##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2 CN                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR384##                                                                            H                          "                "                  "                                                                                    ##STR385##                                                                            CH.sub.3                   "                "                  "     OH       H                          "                                                                                               ##STR386##        "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCl                       "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR387##                                                                            H                          "                "                  "                                                                                    ##STR388##                                                                            CH.sub.3                   "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        C CCH.sub.3                "                "                  "     "        CH.sub.2CCH                 ##STR389##      Me.sub.3 Si CH.sub.2                                                                             CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  CH.sub.2 CH.sub.3                                                                   CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                 ##STR390##                                                                                     ##STR391##        "     "        CCCH.sub.3                 "                "                  "                                                                                    ##STR392##                                                                            H                          "                                                                                               ##STR393##        "     "        "                          "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2 CN                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR394##                                                                            H                          "                "                  "                                                                                    ##STR395##                                                                            CH.sub.3                   "                "                  "     OH       H                          "                                                                                               ##STR396##        "     OH       CCH                        "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CCCH.sub.2 CH.sub.3        "                "                  "     "        CCCCl                      "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR397##                                                                            H                          "                "                  "                                                                                    ##STR398##                                                                            CH.sub.3                   "                "                  CH.sub.2 CH.sub.3                                                                   OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                 ##STR399##                                                                                     ##STR400##        CH.sub.2 CH.sub.3                                                                   CCH      OH                         "                "                  "                                                                                    ##STR401##                                                                            H                          "                                                                                               ##STR402##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR403##                                                                            H                          "                                                                                               ##STR404##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2 CN                "                                                                                               ##STR405##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2CN                 "                "                  "     CCH      OH                         "                                                                                               ##STR406##        "     OH       CCH                        "                "                  "     "        C CCH.sub.3                "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR407##                                                                            H                          "                                                                                               ##STR408##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR409##                                                                                     ##STR410##        CH.sub. 2 CH.sub.3                                                                  CCH      OH                         "                "                  "                                                                                    ##STR411##                                                                            H                          "                                                                                               ##STR412##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR413##                                                                            H                          "                                                                                               ##STR414##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2 CN                "                                                                                               ##STR415##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "         CH.sub.2CN                "                "                  "     CCH      OH                         "                                                                                               ##STR416##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CC       OH                         "                "                  "                                                                                    ##STR417##                                                                            H                          "                                                                                               ##STR418##        "     "        "                          "                "                  "     CC       OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR419##                                                                                     ##STR420##        CH.sub.2 CH.sub.3                                                                   CCH      OH                         "                "                  "                                                                                    ##STR421##                                                                            H                          "                                                                                               ##STR422##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2C CH               "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR423##                                                                            H                          "                                                                                               ##STR424##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2 CN                "                                                                                               ##STR425##        "     "        C CH                       "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2CN                 "                "                  "     CCH      OH                         "                                                                                               ##STR426##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     C CH     OH                         "                "                  "                                                                                    ##STR427##                                                                            H                          "                                                                                               ##STR428##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCH.sub.3                  ##STR429##                                                                                     ##STR430##        CH.sub.2 CH.sub.3                                                                   CCH      OH                         "                "                  "                                                                                    ##STR431##                                                                            H                          "                                                                                               ##STR432##        CH.sub.3                                                                            OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR433##                                                                            H                          "                                                                                               ##STR434##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2 CN                "                                                                                               ##STR435##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     "        CH.sub.2CHCH.sub.2         "                "                  "     "        CH.sub.2CN                 "                "                  "     CCH      OH                         "                                                                                               ##STR436##        "      OH      CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "                                                                                    ##STR437##                                                                            H                          "                                                                                               ##STR438##        "     "        "                          "                "                  "     CCH      OH                         "                "                  "     OH       CCH                        "                "                  "     "        CCCCH.sub.3                 ##STR439##                                                                                     ##STR440##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     "        H                          "                "                  "     "        CH.sub.3                   "                                                                                               ##STR441##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR442##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "     CCCH.sub.3                                                                             OH                          ##STR443##                                                                                     ##STR444##        CH.sub.3                                                                            OH       CH.sub.2C CH               "                "                  "     "        H                          "                "                  "     "        CH.sub.3                   "                                                                                               ##STR445##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR446##        "     OH       C CH                       "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "     CCCH.sub.3                                                                             OH                          ##STR447##                                                                                     ##STR448##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     "        H                          "                "                  "     "        CH.sub.3                   "                                                                                               ##STR449##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR450##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        C CCF.sub.3                "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "     CCCH.sub.3                                                                             OH                          ##STR451##                                                                                     ##STR452##        CH.sub.3                                                                            OH       CH.sub.2CCH                "                "                  "     "        H                          "                "                  ""    CH.sub.3                            "                                                                                               ##STR453##        "     "        CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                                                                                               ##STR454##        "     OH       CCH                        "                "                  "     "        CCCH.sub.3                 "                "                  "     "        CCCF.sub.3                 "                "                  "     "        CH.sub.2CCH                "                "                  "     CCH      OH                         "                "                  "     CCCH.sub.3                                                                             OH                         __________________________________________________________________________

The following compounds are additional compounds falling within thescope of the invention:

(A) compounds of the formula ##STR455##

wherein the A, R₁, R₂, R₃ and R₄ substituents are indicated in thefollowing Table.

    __________________________________________________________________________    A      R.sub.1            R.sub.2                                                                            R.sub.3  R.sub.4                               __________________________________________________________________________            ##STR456##        CH.sub.3                                                                           OH       CCH                                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CCSiMe.sub.3                          "      "                  "    CCH      OH                                    "      "                  "    CCSiMe.sub.3                                                                           OH                                    "      "                  CH.sub.2 CH.sub.3                                                                  OH       CCH                                   "      "                  "    OH       CCCH.sub.3                            "      "                  "    OH       CH.sub.2CCH                           "      "                  CH.sub.3                                                                            ##STR457##                                                                            H                                     "      "                  "    "        OH                                    HON (E)                                                                              "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    CCH      OH                                    "      "                  "    OH       CH.sub.2CCH                           HON (Z)                                                                              "                  "    OH       C CH                                  "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    O                                                                                     ##STR458##        "    OH       CCH                                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCl                                  "      "                  "    "        CCSiMe.sub.3                          "      "                  "    CCH      OH                                    "      "                  "    CCSiMe.sub.OH                                  O                                                                                     ##STR459##        CH.sub.2 CH.sub.3                                                                  OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2C CH                          "      "                  CH.sub.3                                                                            ##STR460##                                                                            H                                     "      "                  "    "        OH                                    "      "                  "                                                                                   ##STR461##                                                                            H                                     HON  (E)                                                                             "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR462##                                                                            H                                     HON (Z)                                                                              "                  "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CH.sub.2 CCH                          "      "                  "    CCH      OH                                    O                                                                                     ##STR463##        "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CH.sub.2 CCH                          "      "                  "    "        CCSiMe.sub.3                          "      "                  "                                                                                   ##STR464##                                                                            H                                     HON (E)                                                                               ##STR465##        CH.sub.3                                                                           OH       C CH                                  "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    HON (Z)                                                                              "                  "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           O                                                                                     ##STR466##        "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCF.sub.3                            "      "                  "    CCSiMe.sub.3                                                                           OH                                    "      "                  "                                                                                   ##STR467##                                                                            H                                     "      "                  "    "        OH                                    "      "                  "                                                                                   ##STR468##                                                                            H                                     "      "                  CH.sub.2 CH.sub.3                                                                  OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CCCH.sub.2CH.sub.3                    "      "                  "    "        CCSiMe.sub.3                          "      "                  "    "        CH.sub.2CCH                           "      "                  "                                                                                   ##STR469##                                                                            H                                     HON (E)                                                                              "                  CH.sub.3                                                                           CCH      OH                                    "      "                  "                                                                                   ##STR470##                                                                            H                                     "      "                  "    OH       CH.sub.2CCH                           HON (Z)                                                                              "                  "    "        "                                     HON (Z)                                                                               ##STR471##        CH.sub.3                                                                           CCH      OH                                    "      "                  "                                                                                   ##STR472##                                                                            H                                     O                                                                                     ##STR473##        "    "          "                                   "      "                  "    CCH      OH                                    "      "                  "    OH       CH.sub.2CCH                           "      "                  "    "        C CCH.sub.2 CH.sub.3                  "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CCH                                   "      "                  "    "        CCSiMe.sub.3                          HON (E)                                                                              "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCl                                  "      "                  "    "        CCSiMe.sub.3                          "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    HON (Z)                                                                              "                  "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2CH.sub.3                    "      "                  "    "        CCCl                                  "      "                  "    "        CCSiMe.sub.3                          "      "                  "    "        CH.sub.2CCH                           O                                                                                     ##STR474##        "    OH       CCH                                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  O                                                                                     ##STR475##        CH.sub.3                                                                           OH       CH.sub.2CCH                           "      "                  "    "        H                                     "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR476##                                                                            H                                     "                                                                                     ##STR477##        "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "                                                                                     ##STR478##        "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        C CCF.sub.3                           "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        H                                     "                                                                                     ##STR479##        "    "        CCH                                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR480##                                                                            H                                     "                                                                                     ##STR481##        "    "        "                                     "      "                  "    C CH     OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "                                                                                     ##STR482##        "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            O                                                                                     ##STR483##        CH.sub.3                                                                           OH       CH.sub.2CCH                           "      "                  "    C CH     OH                                    "      "                  "                                                                                   ##STR484##                                                                            H                                     "                                                                                     ##STR485##        "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCCF.sub.3                            "      "                  "    OH       CCH                                   "      "                  "    "        CH.sub.2 CH CH.sub.2                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2                              "      "                  "                                                                                   ##STR486##                                                                            CH.sub.3                              "      "                  "    OH       CH.sub.2 CN                           HON (E)                                                                              "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR487##                                                                            H                                     HON (Z)                                                                              "                  "    "        "                                     "      "                  "    C CH     OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2CH.sub.3                    "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           O      "                  CH.sub.2 CH.sub.3                                                                  "        CCH                                   "      "                  "    "        CCCH.sub.3                            O                                                                                     ##STR488##        CH.sub.2 CH.sub.3                                                                  OH       CH.sub.2C CH                          "      "                  "    "        CH.sub.2CH CH.sub.2                   "      "                  "                                                                                   ##STR489##                                                                            CH.sub.3                              "      "                  "                                                                                   ##STR490##                                                                            H                                     "      "                  "    CCH      OH                                    "                                                                                     ##STR491##        CH.sub.3                                                                           OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        C CCH.sub.2 CH.sub.3                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CH CH.sub.2                   "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR492##                                                                            H                                     "      "                  "                                                                                   ##STR493##                                                                            CH.sub.3                              "      "                  "                                                                                   ##STR494##                                                                            H                                     "                                                                                     ##STR495##        "    "        "                                     "      "                  "    "        CH.sub.3                              "      "                  "                                                                                   ##STR496##                                                                            H                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CHCH.sub.2                    "                                                                                     ##STR497##        "    "        CCH                                   "      "                  "    "        C CCH.sub.3                           "      "                  "    "        CH.sub.2C CH                          O                                                                                     ##STR498##        CH.sub.3                                                                           CCH      OH                                    "      "                  "                                                                                   ##STR499##                                                                            H                                     "                                                                                     ##STR500##        "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH       OH                                   "      "                  "                                                                                   ##STR501##                                                                            H                                     "                                                                                     ##STR502##        "    OH       CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "                                                                                     ##STR503##        "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    C CH     OH                                    "      "                  "                                                                                   ##STR504##                                                                            H                                     "                                                                                     ##STR505##        "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      Me.sub.3 Si CH.sub.2                                                                             "    "        C CH                                  "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    HON(E) "                  "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            HON(E) Me.sub.3 Si CH.sub.2                                                                             CH.sub.3                                                                           OH       CH.sub.2CCH                           HON(Z) "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           O                                                                                     ##STR506##        "    "        CCCH.sub.3                            "      "                  "                                                                                   ##STR507##                                                                            H                                     "                                                                                     ##STR508##        "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub. 2CHCH.sub.2                   "      "                  "    "        CH.sub.2 CN                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR509##                                                                            H                                     "      "                  "                                                                                   ##STR510##                                                                            CH.sub.3                              "      "                  "    OH       H                                     "                                                                                     ##STR511##        "    OH       CCH                                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR512##                                                                            H                                     "      "                  "                                                                                   ##STR513##                                                                            CH.sub.3                              "      "                  CH.sub.2 CH.sub.3                                                                  OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           O                                                                                     ##STR514##        CH.sub.2 CH.sub.3                                                                  CCH      OH                                    "      "                  "                                                                                   ##STR515##                                                                            H                                     "                                                                                     ##STR516##        CH.sub.3                                                                           OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR517##                                                                            H                                     "                                                                                     ##STR518##        "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "    OH       C CH                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CHCH.sub.2                    "      "                  "    "        CH.sub.2 CN                           "                                                                                     ##STR519##        "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CHCH.sub.2                    "      "                  "    "        CH.sub.2CN                            "      "                  "    CCH      OH                                    "                                                                                     ##STR520##        "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR521##                                                                            H                                     "                                                                                     ##STR522##        "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        C CCH.sub.3                           O                                                                                     ##STR523##        CH.sub.3                                                                           OH       CH.sub.2CCH                           "      "                  "    "        H                                     "      "                  "    "        CH.sub.3                              "                                                                                     ##STR524##        "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "                                                                                     ##STR525##        "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "    CCCH.sub.3                                                                             OH                                    __________________________________________________________________________

(B) compounds of the formula ##STR526##

wherein R₁, R₂, R₃ and R₄ have the definitions in the following Table.

    __________________________________________________________________________    R.sub.1        R.sub.2                                                                          R.sub.3     R.sub.4                                         __________________________________________________________________________     ##STR527##    CH.sub.3                                                                         OH          CCH                                             "              "  "           CCCH.sub.3                                      "              "  "           CCCF.sub.3                                      "              "  "           CH.sub.2 CH.sub.3                               "              "  "           CH.sub.2CCH                                      ##STR528##    CH.sub.3                                                                         CCH         OH                                               ##STR529##    "  OH          CCH                                             "              "  "           CCCH.sub.3                                      "              "  "           CCCF.sub.3                                      "              "  "           CCCH.sub.2 CH.sub.3                             "              "  "           CH.sub.2CCH                                     "              "  "           H                                               "              "  "           CH.sub.2 CH.sub.3                               "              "  CCH         OH                                              "              "                                                                                 ##STR530## H                                               "              "                                                                                 ##STR531## CH.sub.3                                         ##STR532##    "  "             "                                             "              "  OH          C CH                                            "              "  "           CCCH.sub.3                                      "              "  "           CCCF.sub.3                                      "              "  "           CH.sub.2 CH.sub.3                               "              "  "           CH.sub.2CCH                                     "              "  CCH         OH                                              "              "  OH          H                                                ##STR533##    "                                                                                 ##STR534## CH.sub.3                                        "              "  OH          CCH                                             "              "  "           CCCH.sub.3                                      "              "  "           CCCF.sub.3                                      "              "  "           CH.sub.2 CH.sub.3                               "              "  "           CH.sub.2CCH                                      ##STR535##    "  OH          CCH                                             "              "  "           CCCH.sub.3                                       ##STR536##    CH.sub.3                                                                         OH          CCCF.sub.3                                      "              "  "           CH.sub.2CH.sub.3                                "              "  "           CH.sub.2CCH                                     "              "  "           H                                               "              "  "           CH.sub.3                                        "              "  CCH         OH                                              __________________________________________________________________________

In the following examples there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE 1 2,2-dimethyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)

Δ⁴,9 -estradiene-17β-ol-3-one

STEP A:11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-17β(2RS-tetrahydropyranyloxy-Δ⁴,9 -estradiene-3-one

570 mg of p-toluene sulfonic acid were added to a solution of 1.075 g of11β-(4-dimethylaminophenyl -17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one [prepared Example 1 of EPC Application Ser. No.57,115] in 10 ml of tetrahydrofuran and 2 ml of 3,4-dihydro-pyran andthe mixture was stirred at room temperature for one hour. 1 ml oftriethylamine was added to the mixture which was then diluted with ethylacetate. The organic phase was washed with aqueous saturated sodiumbicabonate solution, dried and evaporated to dryness under reducedpressure to obtain 2 g of raw11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)17β-2RS-tetrahydropyranyloxy)-66⁴,9 -estradiene 3-one in the form of a yellow oil.

STEP B:2,2-dimethyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-17.beta.-(2RStetrahydropyranyloxy -Δ⁴,9 -estradiene-3-one

A solution of the product of Step A in 15 ml of anhydroustetrahydrofuran was cooled to -60° C. and over 5 to 6 minutes 1 ml and 3ml of a solution of 2M potassium tert.butylate in tetrahydrofuran and 3ml of a solution of 0.38 of methyl iodide in tetrahydrofuran werealternatively added thereto. The mixture was stirred for another fiveminutes and one ml of triethylamine was added thereto. The temperaturewas allowed-to rise to room temperature and the mixture was evaporatedto dryness to obtain2,2-dimethyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-17.beta.-(2RStetrahydropyranyloxy)-Δ⁴,9 -estradiene-3-one.

STEP C:2,2-dimethyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

2.5 ml of 5N hydrochloric acid were added to a solution of the productof Step B in 10 ml of methanol and after standing for 15 minutes at roomtemperature, the mixture was diluted with water. The methanol wasdistilled off under reduced pressure and 2 5 ml of concentrated ammoniumhydroxide were added thereto. The mixture was vacuum filtered and theproduct was washed with water and dissolved in ethyl acetate. Theorganic phase was dried and evaporated to dryness and the 1.5 g ofresidue were chromatographed over silica gel. Elution with a 9-1benzene-ethyl acetate mixture yielded 990 mg of product which wascrystallized from heptane. The mixture was vacuum filtered and theproduct was washed and dried to obtain 980 mg of2,2-dimethyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl).DELTA.⁴,9-estradiene-17β-ol-3-one melting at 170°-172° C.

A 2.2 g sample of the said product were dissolved in methylene chlorideand the mixture was filtered. The filtrate was evaporated to dryness andthe residue was dissolved in 10 ml of refluxing isopropyl ether and thesolution cooled and crystallization was induced by scraping. The mixturestood at 5° C. and was then vacuum filtered. The product was washed anddried to obtain 1.88 g of the pure product melting. at 171° C. andhaving a specific rotation of [α]_(D) ²⁰ =+183.5°±3.5° (c=1% inchloroform).

Analysis: C₃₁ H₃₉ NO₂, Calculated: %C 81.36 %H 8.59 %N 3.06 Found: 81.1,8.8, 3.2 .

EXAMPLE 2 11β-(4 dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ¹,3,5(10)-estratriene-3,17β-diol and its 17β-acetoxy derivative

2 ml of 98% acetic anhydride and 1 ml of acetyl bromide were addeddropwise under a nitrogen atmosphere to a solution of 2 g of11β-(4-dimethylaminophenyl)-17α-(prop-1 1 ynyl -Δ⁴,9-estradiene-17°-ol-3-one in 20 ml of dry methylene chloride and themixture was stirred at room temperature for one hour. 100 ml of aqueoussodium bicarbonate were added to the mixture which was stirred for 30minutes. The decanted aqueous phase was extracted with methylenechloride and the combined organic phases were dried and evaporated todryness. The 2.65 g of residue were dissolved in 25 ml of methanol and 26 ml of sodium hydroxide solution were added thereto at room temperatureunder nitrogen. The mixture was stirred for 45 minutes and was thenacidified with 14 ml of 2N hydrochloric acid. The mixture was madealkaline by addition of ammonium hydroxide and was extracted withmethylene chloride.

The organic phase was washed with water, dried and evaporated residuewere chromatographed over silica gel and eluted with an 8-2 methylenechloride-ethyl acetate mixture to obtain 430 mg of11β-(4-dimethylaminophenyl) 17α-(prop-1 ynyl)-17β-acetoxy -Δ¹,3,5 (10)-estratriene-3,-ol with an Rf=0.58 and 800 mg of11β-(4-dimethylaminophenyl)-l17α-(prop-1-ynyl)-Δ3,5,(10)-eslratriene-3,17β-diol with an Rf=.0.36.

The 430 mg of the 17β-acetoxy compound were dissolved in 4 ml ofrefluxing methylene chloride and the tion was filtered. 4 ml ofisopropyl ether were added to the filtrate and the mixture wasevaporated to a small volume and iced. The mixture was vacuum filteredand the product was washed with isopropyl ether and dried at 60° C.under reduced pressure to obtain 370 mg of the 17β-acetoxy compoundmelting at 236° C. and having a specific rotation of [α]_(D) ²⁰=194.5°±3°.

Analysis: C₃₁ H₃₇ NO₃, Calculated: %C 78.95, %H 7.91, %N 2.97, Found:78.7, 7.9, 3.0 . l

880 mg of the 3,17β-diol compound from 2 preparations were dissolved in12 ml of refluxing methylene chloride and the mixture was filtered. 12ml of isopropyl ether were added to the filtrate and the mixture wascontrated to a volume of 5 ml. The mixture was iced and vacuum filtereda the product was washed with iced isopropyl ether and dried to obtain770 mg of the 3,17β-diol compound melting at 246° C. and having aspecific rotation of [α]_(D) ²⁰ =-188.5°±2.5°.

Analysis: C₂₉ H₃₅ NO₂, Calculated: %C 81.08, %H 8.21, %N 3.26, Found:81.1, 8.2, 3.1.

EXAMPLE 3 2-(acetyloxymethylene)-11β-(4-dimethylaminophenyl)-17β-(prop-1-ynyl)-Δ⁴,9-estradiene-b 17β-ol-one STEP A: 2-hydroxymethylene-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

5 g of a 55.5% suspension of sodium hydride in oil were washed threetimes with 50 ml of diethyl oxide to remove surnagent and then 100 ml ofdry benzene and 5 g of 11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-66b 4,9-estradiene-17β-ol-3-one were added thereto. 9.4 ml of ethylformate were added thereto dropwise and the mixture was stirred at roomtemperatue for 20 hours and was then poured into 20 ml of water. Themixture was washed three times with 50 ml of diethyl oxide and the washliquids were extracted twice with 50 ml of water. The combined aqueousphases were adjusted to a pH of 3.2 by addition of 70 ml of 2Nhydrochloric acid and then made basic by addition of 40 ml of aqueoussaturated sodium bicarbonate solution. The mixture was extracted oncewith 100 ml and then three times with 50 ml of diethyloxide. Thecombined organic phases were washed with 50 ml of aqueous saturatedsodium chloride solution, dried and evaporated to dryness under reducedpressure to obtain 5.2 g of raw 2-hydroxymethylene-11β-(4-dimethylaminopropyl)-17α-(prop-1-ynyl)-66 ⁴,9-estradiene-17β-ol-3-one which was used as is for the next step.

STEP B: 2-(acetyloxymethylene)-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9 -estradiene-17β-ol-3-one

0.2 ml of pyridine and then 0.16 ml of acetyl chloride were added at 5°C. to a solution of 460 mg of the product of Step A in 20 ml of drychloroform and the mixture stood in an ice bath for one hour after which10 ml of aqueous sodium bicarbonate solution were added thereto. Themixture was stirred for 5 minutes and the decanted aqueous phase waswashed with water, dried and evaporated to dryness under reducedpressure. The 510 mg of residue were dissolved in 10 ml of methylenechloride and 50 mg of activated carbon were added thereto. The mixturewas filtered and the filtrate was evaporated to dryness to obtain 490 mgof product. The latter was empasted with petroleum ether and the productwas washed with petroleum ether and then twice with 5 ml of isopropylether and dried at 50° C. under reduced pressure to obtain 380 mg of2-lacetyloxymethylene)-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+182°±3° (c=1% in chloroform).

Analysis: C₃₂ H₃₇ NO₄, Calculated: %C 76.92, %H 7.46, % N 2.8, Found:77.0, 7.6, 2.6.

EXAMPLE 42-(4-morpholinylmethylene)-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

0.24 ml of morpholine were added to a solution of 1.065 g of2-hydroxymethylene-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one in 10 ml of methanol and the mixture was heatedto 55° C. for one hour and then evaporated to dryness under reducedpressure at 50° C. The 1.25 g of residue was chromatographed overalumina and eluted with a 70-30-1 cyclohexane-acetone-triethylaminemixture to obtain 1.06 g of2-(4-morpholinylmethylene)-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one with a Rf=0.4, and with specific rotation of[α]_(D) ²⁰ =+263°±4.5° (c=0.7% in chloroform).

EXAMPLE 52α-methyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one and its 2β-isomer

A solution of 0.82 ml of cyclohexyl isopropylamine in 5 ml oftetrahydrofuran was slowly introduced at -70° C. under argon to amixture of 3 ml of 1.6M of butyllithium in hexane and 5 ml oftetrahydrofuran and after standing for 10 minutes, a solution of 2.2 gof 11β-(4-dimethylaminophenyl)-17β-(2RS tetrahydropyranyloxy-17α-(prop-1-ynyl)Δ⁴,9 -estradiene-3-one in 8 ml of anhydroustetrahydrofuran was added thereto at -70° C. The mixture stood at -70°C. for 10 minutes and then 0.5 ml of methyl iodide were added thereto.The mixture stood at -70° C. for 30 minutes and then was allowed toreturn to room temperature. One ml of triethylamine was added to themixture which was diluted with ethyl acetate. The organic phase waswashed with water, dried and evaporated to dryness to obtain 2.5 g ofproduct. The latter was dissolved in 25 ml of methanol and 4 ml of 50%hydrochloric acid were added to the mixture which stood at roomtemperature for two hours and was diluted with water. The mixture wasextracted with methylene chloride and the organic phase was washed withwater, dried and evaporated under reduced pressure to obtain 2.04 g ofmixture of the two epimers of2-methyl-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one. The mixture was chromatographed over silicagel and eluted with a 2-3 ether -petroleum ether mixture to obtain 600mg of the 2β-methyl and 345 mg of the 2α-methyl epimer and about 280 mgof the mixture. 1.1 g of the 2β-methyl isomer were crystallized from amethylene chloride-isopropyl ether to obtain 1.04 g of the 2β-methylisomer melting at 211° C. 703 mg of 2α-methyl isomer were crystallizedfrom a methylene chloride-isopropyl ether mixture to obtain 614 mg ofthe product melting at 204° C. Another crystallization of the productgave 560 mg of product melting at 205° C.

Analysis: C₃₀ H₃₇ NO₂, Calculated: %C 81.22, %H 8.40, %N 3.15, Found:2α-isomer: 81.2, 8.5, 3.2, 2β-isomer: 80.8, 8.6, 3.2 .

EXAMPLE 6 11β-(3-methoxyphenyl)-17α-(prop-1-ynyl)-Δ⁵(10)-estrene-17β-ol-3-one STEP A:3,3-ethylenedioxy-11β-(3-methoxyphenyl)-17α-(prop-1-ynyl)-.DELTA.⁹-estrene-5α,17β-diol

A mixture of 33.8 ml of 0.8M of 3-methoxyphenyl magnesium bromide intetrahydrofuran and 285 mg of cuprous chloride was stirred undernitrogen at -20° C. for 15 minutes and a solution of 3.3 g of3,3-ethylenedioxy-5α,10α-epoxy 17α-(prop-1-ynyl)-Δ⁹ (11)-estrene-17β-olin 33 ml of tetrahydrofuran was added over 15 minutes. After a fewminutes, 33 ml of tetrahydrofuran were added and the mixture was stirredat -20° C. for one hour and poured into a mixture of 15 g of ammoniumchloride in 200 ml of iced water. The mixture was stirred for 30 minutesand was extracted three times with ether. The organic phase was washedwith a water, dried and evaporated to dryness under reduced pressure toobtain 5.3 g of residue. The latter was chromatographed over silica geland eluted with a 95-5 methylene chloride-acetone mixture containing 1%of triethylamine to obtain 2.7 g of product with an Rf=30. 200 mg ofproduct were crystallized from an isopropyl ether-methylene chloridemixture to obtain 165 mg of3,3-ethylenedioxy-11β-(3-methoxyphenyl)-17α-(prop-1-ynyl)-.DELTA.⁹-estrene-5α,17β-diol in the form of white crystals melting at 228° C.

Analysis: C₃₀ H₃₈ O₅, Calculated: %C 75.28, %H 8.80, Found: 75.3, 8.1.

STEP B: 11β-(3-methoxyphenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

A mixture of 2.5 g of the product of Step A, 2.5 g of Redex resin and125 ml of 95% ethanol was refluxed with stirring for 90 minutes and wascooled and filtered. The filter was rinsed with 95% ethanol and thefiltrate was evaporated to dryness under reduced pressure to obtain 2.38g of residue. The latter was chromatographed over silica gel and elutedwith a 3-2 petroleum ether-ethyl acetate mixture. The 1.75 g ofamorphous product was crystallized from an ether-cyclo-hexane mixtureand was vaccum filtered. The product was rinsed with cyclohexane anddried under reduced pressure to obtain 1.42 of11β-(3-methoxyphenyl)-17α-(prop-1-ynyl)-Δ⁴,9 -estradiene-17β-ol-3-onemelting at 164° C.

Analysis: C₂₉ H₃₂ O₃, Calculated: %C 80.73, % H 7.74, Found: 80.7, 7.9 .

STEP C:

170 mg of cut lithium were added in small portions at -55° C. to asolution of 20 ml of tetrahydrofuran, 5 ml of tert.-butanol, 4.17 g of11β-(3-methoxyphenyl) 17α-(prop-1-ynyl)-Δ⁴,9 -estradiene-17βol-3-one and100 ml of liquid ammonia and after two hours at -55° C., 50 ml ofaqueous ammonium chloride solution were slowly added thereto. Thetemperature was allowed to rise to room temperature and the mixture wasextracted with ethyl acetate. The organic phase was washed with aqueoussodium chloride solution, dried and evaporated to dryness to obtain 4.3g of resin. The latter was chromatographed over silica gel and elutedwith a 7-3 cyclohexane-ethyl acetate mixture to obtain 380 mg of11β-(3-methoxyphenyl)-17α-(E)-(prop-1-enyl)- ⁵,(10)-estrene-17β-ol-3-one with a Rf=0.27 and a specific rotation of[α]_(D).sup.° =+10.5°±1° (c=1.2% in chloroform) and 2.65 g of11β-(3-methoxyphenyl)-17α-(prop-1-ynyl)-Δ⁵(10)estrene- 17β-ol-3-one withan Rf=0.25 and a specific rotation of ∂α]_(D) ²⁰ =-30°±1.5° (c=1% inchloroform).

Analysis: 17α-(prop-1-enyl) C₂₈ H₃₆ O₃, Calculated: %C 79.96, %H 8.63,Found: 79.8, 8.9 .

Analysis: 17α-(prop-1-ynyl) C₂₈ H₃₄ O₃, Calculated: %C 80.34, %H 8.19,Found: 80.4, 8.3.

EXAMPLE 7 11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-isoxazolo[4,5-b]Δ⁴,9 -estradiene-17β-ol

350 mg of hydroxylamine hydrochloride were added to a solution of 1.2 gof 2-hydroxymethylene-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one in 6 ml of tert.-butanol and the mixture wasrefluxed for 10 minutes, cooled and diluted with water. The mixture wasextracted with methylene chloride and the organic phase was washed,dried and evaporated to dryness under reduced pressure. The 1.23 g ofresidue was chromatographed over 90 g of silica gel and eluted with a4-6 petroleum ether-ether mixture to obtain 755 mg of11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-isoxazolo [4,5-b]-Δ⁴,9-estradiene-17β-ol.

EXAMPLE 82-cyano-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

Nitrogen was bubbled at room temperature through a solution of 1.2 g ofthe product of Step A of Example 7 in 10 ml of methanol for 15 minutesand 3 ml of N potassium hydroxide solution were added thereto. Thesolution stood under nitrogen at room temperature for three hours andwas diluted with water. The mixture was extracted with methylenechloride and the organic phase was washed with water, dried andevaporated to dryness under reduced pressure. The 1.19 g of residue waschromatographed over silica gel and eluted with a 7-3 ether-petroleumether mixture to obtain 685 mg of2-cyano-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one.

Analysis: C₃₀ H₃₄ O₂ N₂ 1/4H₂ O, Calculated: %C 78.48, %H 7.57, %N 6.10%H₂ O≃1, Found: 78.2, 7.6, 5.9, ≃0.8.

EXAMPLE 92,2-dicyano-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

4.4 ml of a solution of 1.6M of butyllithium in hexane were added undernitrogen to 10 ml of anhydrous tetrahydrofuran and after cooling themixture to -70° C., a solution of 1.15 ml of N-cyclohexyl-isopropylamincin 15 ml of anhydrous tetrahydrofuran was added thereto. The solutionwas cooled to -70° C. and a solution of 1.290 g of11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one in 12 ml of tetrahydrofuran was added theretoto obtain solution A.

Solution A was added dropwise at -60° C. to a solution of 2.55 g oftosyl cyanide in 15 ml of tetrahydrofuran and the mixture stood at -60°C. for 40 minutes and then allowed to rise to room temperature. Themixture was poured into water and was extracted with ethyl acetate. Theorganic phase was washed, dried and evaporated to dryness under reducedpressure and the 2.85 g of residue were chromatographed over 80 g ofsilica gel. Elution with a 4-1 benzene-ethyl acetate mixture yielded1.06 g of product which was crystallized from a methylenechloride-isopropyl ether mixture to obtain 774 mg of2,2-dicyano-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one melting at 265° C.

Analysis: CX₃₁ H₃₃ N₃ O₂, Calculated: %C 77.63,%H 6.93, %N 8.76, Found:77.6, 7.0, 8.7.

EXAMPLE 10 11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁵(10)-estrene-17β-ol-3-one

15 ml of anhydrous tetrahydrofuran and 2.5 ml of tert.-butanol wereadded to liquid ammonia at -60° C. and then 2.15 g of11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one were added thereto. 80 mg of lithium were addedto the solution in 6 fractions over 30 minutes and after another 30minutes at -60° C., the mixture was placed in an ice bath. 40 ml of anaqueous solution of 100 g/l of ammonium chloride were slowly added tothe mixture which was stirred at room temperature for 30 minutes. Themixture was extracted with ethyl acetate and the organic phase waswashed with aqueous ammonium chloride solution, dried and evaporated todryness. The 2.3 g of residue were chromatographed over 90 g of silicagel and eluted with a 4-1 benzene-ethyl acetate mixture to obtain 1.67 gof 11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ⁵(10)-estrene-17β-ol-3-one. An analytical sample which was obtained by chromatographyover silica gel and elution with a 2-1 ether-heptane mixture had aspecific rotation [α]_(D) ²⁰ =-68.5°±2.0 (c=1% in chloroform).

Analysis: C₂₉ H₃₇ NO₂, Calculated: %C 80.7, %H 8.64, %N 3.25, Found: 806, 8.90, 3.05.

EXAMPLE 113-methoxy-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ.sup.1,3,5(10)-estratriene-17β-ol

0.06 ml of methyl sulfate were added all at once to a solution of 215 mgof 11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ¹,3,5(10)-estratriene-3,17β-diol, 6 ml of 0.1N sodium hydroxide solution and 6 mlof acetone cooled in an ice bath and the mixture was removed from theice bath, stirred for 21/2 hours and then was diluted with 30 ml ofethyl acetate. The decanted organic phase was washed with aqueous sodiumchloride solution, dried and evaporated to dryness under reducedpressure. The 155 mg of residue were chromatographed over silica gel andeluted with a 3-2 petroleum ether-ethyl acetate mixture afterdissolution in methylene chloride to obtain 120 mg of3-methoxy-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ¹,3,5(10)-estratriene-17β-ol with an Rf=0.4.

EXAMPLE 123-methoxy-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-17β-acetoxy-Δ¹,3,5(10)-estratriene

0.08 ml of methyl sulfate were added with stirring under nitrogen to amixture of 330 mg of 11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-17β-acetoxy-Δ¹,3,5(10)-estratriene- 3-ol, 1.65ml of acetone, 0.33 ml of water and 0.42 ml of 2N sodium hydroxidesolution and the mixture was stirred for one hour and was diluted withwater. The mixture was extracted with ethyl acetate and the organicphase was dried and evaporated to dryness under reduced pressure. Theresidue was chromatographed over silica gel and eluted with a 4-1cyclohexane-ethyl acetate mixture to obtain 220 mg of3-methoxy-11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-17.beta.-acetoxy-Δ¹,3,5(10)-estratriene.

EXAMPLE 13 11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10)-estratriene-3,17β-diol STEP A:3,3-ethylenedioxy-11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ.sup.9-estrene-5α-ol 17-one

A solution of 97.4 g of 4-bromo-4-(2-dimethylaminoethoxy)-benzene in 480ml of tetrahydrofuran was added at about 35° C. over 75 minutes to amixture of 11.5 g of magnesium turnings and 20 ml of tetrahydrofuran andthe mixture was stirred for one hour and 380 ml of the solution werepoured into a suspension of 23.5 g of a complex of CuBr.(CH₃)₂ S and 235ml of tetrahydrofuran. After stirring for 15 minutes at roomtemperature, a solution of 30 g of 3,3-ethylenedioxy-5α,10α-epoxy-Δ⁹(11)-estrene-17-one [described in EPC application No. 57,115] in 150 ml oftetrahydrofuran was added to the mixture over 20 minutes and the mixturewas stirred at room temperature for 16 hours and was poured into 3liters of aqueous saturated ammonium chloride solution. The mixture wasextracted with ether and the organic phase was washed with aqueoussaturated ammonium chloride solution, then with aqueous saturated sodiumchloride solution, dried and evaporated to dryness under reducedpressure. The 66.7 g of residue were chromatographed over silica gel andeluted with a 9-1 chloroform-methanol mixture containing 1% oftriethylamine and then over alumina and eluted with an 8-2 benzene-ethylacetate mixture to obtain 30.65 g of3,3-ethylenedioxy-11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ.sup.9-estrene-5α-ol-17-one.

STEP B: 11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ⁴,9-estradiene-3,17-dione

A mixture of 5 g of the product of Step A, 100 ml of methanol and 15 mlof 2N hydrochloric acid was stirred at room temperature for 3 hours andwas then poured into 400 ml of ether. The mixture was made alkaline bythe addition of 100 ml of 0.5M sodium bicarbonate solution and wasstirred for 15 minutes. The decanted aqueous phase was extracted withether and the organic phase was washed with aqueous saturated sodiumchloride solution, dried and evaporated to dryness under reducedpressure. The 3.90 g of product were empasted with a minimum ofisopropyl ether 3 times to obtain 3.10 g of11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ⁴,9 -estradiene3,17-dionemelting at 206° C.

STEP C: 11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10)-estratriene-3-ol-17-one

A mixture of 4 g of acetic anhydride and 2 ml of acetyl bromide wasadded at 0° to 5° C. to a solution of 4 g of the product of Step B in 40ml of methylene chloride and the mixture was allowed to rise to roomtemperature and was then stirred for 2 hours. The mixture was pouredinto 200 ml of aqueous saturated sodium bicarbonate solution and wasstirred for 15 minutes. The mixture was extracted with methylenechloride and the organic phase was washed with water, dried andevaporated to dryness under reduced pressure. The 4.33 g of residue weredissolved in 40 ml of methanol and after the addition of 4 ml of sodiumhydroxide, the mixture was stirred for 90 minutes at room temperatureand was poured into 200 ml of water. The mixture was adjusted to a pH of≃2 by addition of 30 ml of 2N hydrochloric acid and was then adjusted toa pH of ≃9 by addition of 5 ml of ammonium hydroxide. The mixture wasextracted with methylene chloride and the organic phase was washed withwater, dried and evaporated to dryness under reduced pressure. Theresidue was chromatographed over silica gel and was eluted with a 9-1methylene chloride-methanol mixture to obtain 2.6 g of 11β-[4-(2-dimethylamino ethoxy) phenyl]-Δ¹,3,5(10)-estratriene-3-ol-17-one.

STEP D: 11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10)-estratriene-3,17β-diol

545 mg of sodium borohydride were added in small fractions to a mixtureof 2.1 g of the product of Step C and 21 ml of methanol and the mixturewas stirred at room temperature for one hour and was poured into 210 mlof a mixture of ice and water. The mixture was extracted with methylenechloride and the organic phase was washed with aqueous saturated sodiumchloride solution, dried and evaporated to dryness under reducedpressure. The residue was chromatographed over silica gel and elutedwith an 8-2 acetone-methanol mixture to obtain 1.37 g of product whichwas crystallized from a methylene chloride-isopropyl ether to obtain1.27 g of 11β-[4-(2-dimethylaminomethoxy)-phenyl]-Δ¹,3,5(10)-estratriene-3,17-diol melting at 130° C. and having a specific rotationof [α]_(D) ²⁰ =-46.5°±1.5° (c=0.8% in chloroform).

EXAMPLE 1411β-[4-2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10)-estratriene - 17β-olSTEP A: A AND B isomers of 11β-[4-(2-dimethylaminoethoxy)phenyl]-Δ⁴,9-estradiene-3,17β-diol

1.74 g of sodium borohydride were added in small fractions over 20minutes to a solution of 5 g of 11β-[4-(2-dimethylaminoethoxy)-phenyl]Δ⁴,9 -estradiene-3,17-dione in 100 ml of methanol and themixture was stirred at room temperature for one hour and was poured into750 ml of ice and water. The mixture was stirred for 30 minutes and wasvacuum filtered. The product was washed until the wash water was neutraland dried to obtain 4.6 g of A and B isomers of11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ⁴,9 -estradiene-3,17β-diolmelting at 110° C.

STEP B: 11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10)-estratriene-17β-ol

A mixture of 1 g of the product of Step A, 20 ml of tetrahydrofuran and1 ml of 6N hydrochloric acid was stirred at room temperature for 3 hoursand was poured into 200 ml of aqueous saturated sodium bicarbonatesolution. The mixture was extracted with ethyl acetate and the organicphase washed with aqueous saturated sodium chloride solution, dried andevaporated to dryness under reduced pressure. The residue waschromatographed over silica gel and eluted with an 8-2 petroleumether-acetone mixture to obtain 325 mg of product which was dissolved ina 1-1 methylene chloride-isipropyl ether mixture. The solution wasslowly concentrated to half its volume to obtain 300.5 mg of11β-[4-(2-dimethylaminoethoxy)-phenyl]-Δ¹,3,5(10)-estratriene- 17β-olmelting at 155° C. and having a specific rotation of [α]_(D) ²⁰=-38.5°±2° (c=0.8% in chloroform).

EXAMPLE 15 3-(2-dimethylamino-ethoxy)-11β-phenyl-Δ¹,3,5(10)-estratriene-17β-ol STEP A: 3,3-ethylenedioxy-11β-phenyl-Δ⁹ -estrene-5α-ol-17one

80 g of bromobenzene, were added over 70 minutes to a refluxing mixtureof 13 g of magnesium turnings and 30 ml of tetrahydrofuran and themixture was allowed to return to 20° C. with stirring. The mixture wascooled to -25° C. to obtain 330 ml of a solution of 0.85M of phenylmagnesium bromide. 4.165 g of cuprous chloride were added thereto all atonce and the mixture was stirred at -25° C. for 10 minutes after which asolution of 11.5 g of 3,3-ethylenedioxy-5α,10α-epoxy-Δ⁹(11)-estrene-17-one in 60 ml of tetrahydrofuran was added dropwise at -25°C. over 20 minutes. The mixture was held at -25° C. for two hours andwas then poured into a mixture of 600 ml of ice and 45 g of ammoniumchloride. The mixture was stirred for 30 minutes and was extracted withether. The organic phase was washed with water, dried and evaporated todryness under reduced pressure. The residue was chromatographed oversilica gel and eluted with a 6-4 benzene-ethyl acetate mixture contain1% of triethylamine to obtain 7.86 g of 3,3-ethylenedixoy-11β-phenyl-Δ⁹-estrene-5α-ol-17-one melting at 173° C. and having a specific rotationof [α]_(D) ²⁰ =+54.5°±1.5° (c=1% in chloroform).

STEP B: 11β-phenyl-Δ⁴,9 -estradiene-3,17-dione

A mixture of 7.4 g of the product of Step A in 225 ml of 95% ethanol washeated to 40° C. and 7.4 g of redex CF resin were added thereto all atonce. The mixture was refluxed with stirring under an inert gas for onehour and was filtered. The product was empasted four times with 20 ml of95% ethanol and the filtrate was evaporated to dryness under reducedpressure. The 6.5 g of resin were chromatographed over silica gel andeluted with a 9-1 chloroform-ethyl acetate mixture. The 486 mg ofproduct were dissolved at reflux in a mixture of 12.5 ml of isopropylether and 3 ml of methylene chloride and the mixture was filtered hot.The filtrate was concentrated to a small volume and crystallization wasrefluxed was effected. The mixture was vacuum filtered and the productwas washed with isopropyl ether to obtain 369.4 mg of 11β-phenyl-Δ⁴,9-estradiene-3,17-one melting at a 197° C. and having a specific rotationof [α]_(D) ²⁰ +223°±3° (c=0.5% in chloroform).

STEP C: 11β-phenyl-Δ¹,3,5(10) -estratriene-3-ol-17-one

A mixture of 3.75 ml of acetic anhydride and 1.9 ml of acety) bromidewas added dropwise with stirring at 0° C. to a solution of 3.76 g of theproduct of Step B in 26.3 ml of methylene chloride and the mixture wasstirred at room temperature for 75 minutes and was added dropwise withstirring to 90 ml of aqueous saturated sodium bicarbonate solution.After stirring for 15 minutes, the mixture was extracted with methylenechloride and the organic phase was washed with water, dried andevaporated to dryness under reduced pressure. The residue was added to26.3 ml of methanol and then 18.8 ml of sodium hydroxide solution wereadded thereto. The mixture was stirred for 16 hours and was acidified toa pH of about 1 at approximately 20° C. by addition of 40 ml of sulfuricacid diluted to one-fifth. The mixture was stirred for 20 minutes andwas then vacuum filtered. The product was empasted four times with 25 mlof water to obtain 4.030 g of product which was crystallized frommethylene chloride to obtain 3.01 g of11β-phenyl-Δ¹,3,5(10)-estratriene- 3-ol-17-one melting at 290° C. andhaving a specific rotation of [α]_(D).sup.° =-9° ±2° (c =0.5% inchloroform).

STEP D: 11β-phenyl-Δ¹,3,5(10)-estratriene- 3,17β-diol

144 mg of sodium borohydride were added over 10 minutes under an inertatmosphere with stirring to a mixture and after stirring at 50° C. forone hour, the mixture was cooled to 20° C. The pH was adjusted to 5 bydropwise addition of 0.4 ml of acetic acid and the mixture was stirredfor 10 minutes and poured into 30 ml of ice and water. The mixture wasstirred for 30 minutes and was vacuum filtered. The product was empastedwith water and dried to obtain 896 mg of11β-phenyl-Δ¹,3,5(10)-estratriene- 3,17β-diol melting at 228° C. andhaving a specific rotation of [α]_(D).sup.° -34° ±2° (c =0.5% inchloroform).

STEP E: 3 (2-dimethylaminoethoxy)-11β-phenyl-Δ¹,3,5(10)-estratriene-17β-ol

3.5 ml of an 95% ethanolic solution of N sodium hydroxide were added allat once to a mixture of 1.220 g of the product of Step D and 12.2 ml of95% othanol and the mixture was heated to 60° C after which a solutionof the amine prepared from 555 mg of dimethylamino-2-chlorethanehydrochloride in 1.7 of 95% ethanol was added all at,once. The mixturewas neutralized by the addition of freshly prepared 3 85 ml of N sodiumhydrodide in 95% ethanol and the mixture was refluxed with stirringunder an inert atmosphere for 90 minutes and was cooled to 20° C. andfiltered. The product was empasted with 10 ml of 95% ethanol and thefiltrate was evaporated to dryness. The residue and 20 ml of methylenechloride and 20 ml of water was stirred for 10 minutes and the decantedaqueous phase was extracted with methylene chloride. The organic phasewas washed with water, dried and evaporated to dryness under reducedpressure. The 1.61 g of residue was chromatographed over silica gel andeluted with 6-4 chloroformmethanol mixture to obtain 939 mg of3-(2-dimethylaminoethoxy) 11β-phenyl-Δ¹,3,5(10) -estratriene-17β-ol witha specific rotation of [α]_(D) ²⁰ =-32° ±2° (c =0.7% in chloroform).

EXAMPLE 16 11β-(4-pyridyl)-17α-(prop-1-ynyl-Δ⁴,9-estradiene-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-17α-(prop-1-ynyl)-Δ⁵(10),9(11)-estradiene-17β-ol

207 ml of a solution of 1 5% ethyl magnesium bromide in tetrahydrofuranwere stirred at 0° C. while bubbling gaseous propyne dried over calciumchloride therethrough for 90 minutes and the temperature was thenallowed to return to room temperature. The mixture was stirred for onehour while the bubbling was continued. Then a solution of 30 g of3,3-[1,2-ethanediyl-bisoxy]Δ⁵(10), 9(11) -estradiene-17-one in 120 ml ofanhydrous tetrahydrofuran and one drop of triethylamine was added to themixture over 30 minutes and the mixture was stirred for 2 hours at roomtemperature and was then poured into a mixture of ice, distilled waterand ammonium chloride. The stirred mixture was extracted 3 times withether and the organic phase was washed with water, dried and evaporatedto dryness under reduced pressure. The residue was dried under reducedpressure to obtain 35.25 g of3,3-[1,2-ethanediyl-bisoxy]-17α-(prop-1-ynyl)0Δ⁵(10), 9(11)-estradiene-17β-ol.

NMR Spectrum (deuterochloroform):

Peaks at 0.83 ppm hydrogens of 18-methyl}; at 1.85 ppm (hydrogens ofmethyl of C.tbd.C═CH₃); at 5.65 ppm (hydrogens of 11-carbon); at 4 ppm(hydrogens of ethylene ketal).

STEP B: 3,3-[1,2-ethanediyl-bisoxy]- 5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11) -estrene-17β-ol

A mixture of 30 g of the product of Step A in 150 ml of methylenechoride was stirred while bubbling nitrogen therethrough and aftercooling the mixture to 0° C., 1.8 ml of hexafluoroacetone sesquihydratewere added all at once. The mixture was stirred while 4.35 ml of 85%oxygenated water were added and the mixture was stirred at 0° C. for 72hours while continuing to bubble nitrogen therethrough. The solution waspoured into a mixture of 250 g of ice and 500 ml of 0.2N sodiumthiosulfate solution and the mixture was stirred for a few moments andwas then extracted with methylene chloride. The organic phase was washedwith distilled water, dried over sodium, sulfate in the presence ofpyridine and evaporated to dryness under reduced pressure. The residuewas dried under reduced pressure and the 31.6 g of residue were oversilica gel. Elution with a 9-1 benzeneethyl acetate mixture yield3,3-[1,2-ethanediyl-bisoxy]-5α10α-epoxy17 α(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol.

NMR Spectrum (deuterochloroform):

Peaks at 0.82 ppm (hydrogens of 18-CH₃); at 1.83 ppm (hydrogens ofmethyl of C.tbd.C--CH₃); at 6.1 ppm (hydrogens of 11-carbon); at 3.92ppm (hydrogens of ethylene ketal).

STEP C:3,3-[1,2-ethanediyl-bisoxy]-11β-(4-pyridyl)-17α-(prop-1-ynyl)-.DELTA.⁹-estrene-5α,17β-diol

100 ml of a tetrahydrofuran solution of 0.5 to 0.6 M 4-chloropyridylmagnesium bromide prepared from 15 g of 4-chloro-pyridine and 6 g ofmagnesium was added at 20° C. to a solution of 6.16 g of dimethylsulfide-cuprous bromide complex in 40 ml of tetrahydrofuran and themixture was stirred under an inert atmosphere at room temperature for 20minutes. Then a solution containing 3.7 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17β-(prop-1-ynyl)-Δ⁹(11)-estrene 17β-ol was added thereto over 10 minutes and the mixture wasstirred at room temperature for one hour and was then poured into amixture of cold water and ammonium chloride. The mixture was stirred atroom temperature for 30 minutes and was extracted with ether. Theorganic phase was washed with an aqueous saturated sodium chloridesolution, was dried and evaporated to dryness under reduced pressure.The 6 g of residue were chromatographed over silica gel and eluted witha 1-1 methylene chloride-acetone mixture containing 1 ppm oftriethylamine to obtain 3.15 g of 3,3-[12-ethanediyl-bisoxy]11β-(4-pyridyl)-17α-(prop-1-ynyl)-Δ.sup.9-estrene-5α,17β-diol which was dried towards 60° C. at 0.1 mm Hg whichhad a specific rotation of [α]_(D) ²⁰ =-52° ±1 5° (c =1% in chloroform).

STEP D: 11β-(4-pyridyl)-17α-(prop-1-ynyl)-Δ⁴,9 -estradiene-17β-ol-3-one

A solution of 2.9 g of the product of Step C, 14 ml of methanol and 7 mlof 2N hydrochloric acid was stirred under an inert atmosphere at roomtemperature for 3 hours and was then admixed with a solution of 200 mlof ether and 90 ml of aqueous saturated sodium bicarbonate solution. Themixture was stirred at room temperature for 15 minutes and the decantedted aqueous phase was extracted with ether. The organic phase was washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness under reduced pressure. The of residue were chromatographed oversilica gel and eluted with a 6-4 methylene chloride-acetone mixture. The1.7 g of product was dried for 24 hours at 0 1 mm Hg and for 8 hours at80° C. to obtain 11β-(4-pyridyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one with specific rotation of [α]_(D) ²⁰ =+30.5°±1°(c=1% in chloroform).

Using the same procedure, 11β-(3-pyridyl) 17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =+14°(c=1% in chloroform) and 11β-(2-pyridyl)-17α-(prop-1-yl)-Δ⁴,9estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =-2°(c=1% in chloroform) were prepared.

EXAMPLE 17 11β[3-(N,N-dimethylamino)-propyl]-17α-(prop-1 ynyl)-Δ⁴,9-estradiene-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-propyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5.sub.α,17.sub.β -diol

12.33 g of dimethyl sulfide-cuprous bromide complex were added over 5minutes at 0° C. to a solution of 0.85M of 3-(N,N-dimethylamino)-propylmagnesium chloride [prepared from 42 g of chloro3-(N,N-dimethylamino)-propane and 10.5 g of magnesium] and the mixturewas stirred at 0° C. for 25 minutes. A solution of 3.70 g of3,3-[1,2-ethanediyl-bisoxy]-5.sub.α,10.sub.α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11) -estrene-17β-ol in 50 ml oftetrahydrofuran was added to the mixture dropwise and the mixture wasthen stirred at 0° C. for 3 hours and was poured into a mixture of 40 gof ammonium chloride and 200 ml of iced water. The mixture was stirredat room temperature for 15 minutes and was then extracted with ether.The organic phase was washed with aqueous saturated sodium chloridesolution, dried, and evaporated to dryness under reduced pressure. The4.6 g of residue were chromatographed over silica gel and eluted with an8-2 methylene-chloride-methanol mixture to obtain 2.55 g of3,3-[1,2-ethandiyl-bisoxy]-11β-[3(N,N-dimethylamino)-propyl]-17α-(prop-1-ynyl)-Δ⁹ -estrene-5α,17β-diolwith a specific rotation of [α]_(D) ²⁰ =-86°±1.5° (c=1% in chloroform).

STEP B: 11β-[3-(N,N-dimethylamino)-propyl]-17α-(prop-1-ynyl)-β.sup.4,9-estradiene-17β-ol-3-one

A mixture of 2.4 g of the product of Step A, 14 ml of methanol and 7 mlof 2N hydrochloric acid was stirred under an inert atmosphere at roomtemperature for 4 hours and then 200 ml of isopropyl ether and 90 ofaqueous saturated sodium bicarbonate solution were added thereto. Themixture was stirred at room temperature for 30 minutes and the decantedaqueous phase was extracted with ether. The organic extract was washedwith aqueous saturated sodium chloride solution, was dried andevaporated to dryness under reduced pressure. The 1.8 g of residue werechromatographed over silica gel and eluted with an 8-2chloroform-methanol mixture The 1.30 g of product were dried at 30 to40° C. at 0.1 mm Hg to obtain 1.25 g of11β-[3-(N,N-dimethylamino)-propyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =-114° ±2.5° (c=1% in chloroform).

EXAMPLE 18 11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop1-ynyl)-Δ⁴,9 -estradiene-17β-ol-3-one STEPA:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 24 g of 4-(N,N-dimethylaminoethoxy)bromobenzene was addeddropwise over 45 minutes to 90 ml of anhydrous tetrahydrofuran and 2 mlof 1-dibromoethane were added as catalyst. After the addition, themixture was stirred at 25° C. hour to obtain a solution of 0.7M of4-(N,N-dimethylaminoethoxy)-bromobenzene magnesium which was then addedto a solution of 6.16 g of dimethylsulfide-cuprous bromide complex in 20ml of tetrahydrofuran. The mixture was stirred at room temperature for20 minutes and a solution of 3.7 g of3,3-[1,2-(ethanediyl-bisoxy)-]-5α,10α-epoxy-17α-prop 1-ynyl-Δ⁹(11)-estrene-17β-ol in 50 ml of tetrahydrofuran was added thereto dropwiseover a few minutes. The mixture may stirred under an inert atmospherefor one hour and was then poured into a solution of 15 g of ammoniumchloride in 20 ml of iced water. The mixture was extracted with etherand the organic phase was washed with aqueous saturated sodium chloridesolution, was dried and evaporated to dryness under reduced pressure.The 18.3 g of oil were chromatographed over silica gel and eluted withchloroform to obtain 4.5 g of3,3-[1,2-ethanediyl-bisoxyl-11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol with a specific rotation of [α]_(D) ²⁰ =-44°±1.5°(c=1% in chloroform).

STEP B: 11β-[4-(N,N-dimethylaminoethoxy]-phenyl]-17α-(prop 1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

9.5 ml of 2N hydrochloric acid were added to a solution of 4.5 g of theproduct of Step A in 20 ml of methanol and the solution was stirred atroom temperature for 2 hours. 260 ml of ether and 110 ml of an aqueoussaturated sodium bicarbonate solution were added to the mixture whichwas stirred at room temperature for 15 minutes. The decanted aqueousphase was extracted with ether and the organic phase was dried andevaporated to dryness under reduced pressure. The 3.3 g of residue werechromatographed over silica gel and eluted with a 92.5-7.5 methylenechloride-methanol mixture to obtain 1.8 g of amorphous11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =+71°(c=1% in chloroform).

EXAMPLE 1911β-[4,-[N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 38 mmoles of p-dimethylaminophenyl magnesium bromide intetrahydrofuran was added to a suspension of 4.1 g of a cuprousbromide-dimethylsulfide complex in 20 ml of tetrahydrofuran and then asolution of 2.45 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10β-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)estrene -17β-ol-in tetrahydrofuran was added thereto. The mixture wasstirred for 10 minutes and was then hydrolyzed with 50 ml of aqueoussaturated ammonium chloride solution. The decanted aqueous phase wasextracted with ether and the organic phase was washed with water, driedand evaporated to dryness under reduced pressure. The 11 g of residuewere chromatographed over silica gel and eluted with a 6-4cyclohexane-ethyl acetate mixture to obtain 1.8 g of3,3-[1,2-ethanediylbisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol which after crystallization from isopropyl etherand ethyl acetate had a specific rotation of [α]_(D) ²⁰ =- 66.5° (c=1%in chloroform) and a melting point of 210° C., and 750 m of thecorresponding 11α-compound.

STEP B: 11β8-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

2 ml of concentrated hydrochloric acid were added to a solution of 1.53g of the product of Step A in 60 ml of methanol and after stirring themixture for 30 minutes at room temperature, 150 ml of ether and then 50ml of aqueous N sodium hydroxide solution were added thereto. Thereaction mixture was stirred for 15 minutes and the decanted organicphase was dried and evaporated to dryness under reduced pressure. The1.4 g of residue were chromatographed over silica gel and was elutedwith a 7-3 cyclohexane-ethyl acetate mixture to obtain 0.932 g of118-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9 -estradiene17β-ol-3-one melting at 150° C. and a specific rotation of [α]_(D) ²⁰=+138.5° (c=0.5% in chloroform).

EXAMPLE 20 11β-[4-trimethylsilyl-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9estradiene-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-(4-trimethylsilylphenyl)-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

200 mg of cuprous chloride were added under an inert atmospheric at -30°C. to 45 ml of solution of 0.65M of 4-trimethylsilyl-phenyl magnesiumbromide in tetrahydrofuran and a solution of 3.3 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10β-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol in 25 ml of tetrahydrofuran were added thereto dropwiseat -20° C. After one hour, the mixture was hydrolyzed with aqueousammonium chloride solution and was extracted with ether. The organicphase was dried and evaporated to dryness under reduced pressure and theresidue was chromatographed over silica gel. Elution with a 94-6methylene chloride-acetone mixture containing 0.1% of triethylamineyielded 2.087 g of3,3-[1,2-ethanediyl-bisoxy]-11β-(4-trimethylsilyl-phenyl)-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol which after crystallization from isopropyl etherand then ethyl acetate melted at 226° C. and a specific rotation of[α]_(D) ²⁰ =-60°±1.5° (c=0.9% in chloroform).

STEP B: 11β-(4-trimethylsilyl-phenyl) 17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

1.7 g of Redex sulfonic acid resin were added to a solution of 1.68 g ofthe product of Step A in 17 ml of 90% alcohol and the mixture wasrefluxed for 30 minutes and vacuum filtered. The filter was rinsed withmethylene chloride and the filtrate was evaporated to dryness underreduced pressure. The residue was taken up in methylene chloride and thesolution was dried and evaporated to dryness under reduced pressure. Theresidue was chromatographed over silica gel and was eluted with an 85-15benzene-ethyl acetate mixture to obtain 1.217 g of11β-(4-trimethylsilyl-phenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one melting at 212° C. and having a specificrotation of [α]_(D) ²⁰ =+94° (c=0.9% in chloroform).

The same procedure was used to prepare11β-[3-trimethylsulyl-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol 3-one with a specific rotation of [α]_(D) ²⁰=+52.5°±2° (c=1% in chloroform).

EXAMPLE 21 11β-[4-(N,N-dimethylamino)-phenyl]-17β-ethynyl-Δ⁴,9-estradiene-17α-ol-3-one STEP A: 3,3-dimethoxy-17β-ethynyl-Δ⁵(10),9(11)-estradiene -17α-ol

A mixture of 16.8 g of 3,3-dimethoxy-17α-ethynyl-Δ⁵(10),9(11)-estradiene-17β-ol, 175 ml of anhydrous tetrahydrofuran and 4.35 g oflithium bromide was stirred at room temperature for 5 minutes and thenthe mixture was cooled to -60° C. and 3.9 ml of methane sulfonylchloride were added thereto. The mixture was stirred at -60° C. for onehour and was then poured into 500 ml of aqueous saturated ammoniumchloride solution. The mixture was stirred for 10 minutes and wasextracted with methylene chloride. The organic phase was dried and afterthe addition of 2.5 ml of pyridine, the mixture was evaporated todryness at 0° C. under reduced pressure. 75 ml of tetrahydrofuran wereadded to the residue and 12.5 ml of 0.75 g of silver nitrate in waterwere added thereto. The mixture was held at -30° C. for 18 hours and atroom temperature for 4 hours and then poured into 500 ml of aqueoussemisaturated ammonium chloride solution containing 5 g of sodiumcyanide. The mixture was stirred at 20° C. for 30 minutes and wasextracted with chloroform. The organic phase was washed with aqueoussaturated sodium chloride solution, dried and evaporated to drynessunder reduced pressure. The residue was chromatographed over silica geland was eluted with a 9-1 petroleum ether-ethyl acetate mixture toobtain 3 g of 3,3-dimethoxy-17β-ethynyl-Δ⁵(10),9(11) -estradiene-17α-olmelting at ˜150° C. and having a specific rotation of [α]_(D) ²⁰=+125°±2.5° (c=1% in chloroform).

STEP B: 3,3-dimethoxy-5α,10α-epoxy-17 β-ethynyl-Δ⁹(11) -estrene-17α-ol

0.12 ml of hexachloroacetone and 0.65 ml of oxygenated water (200volumes) were added at 0° C. to a mixture of 2.6 g of the product ofStep A, 12 ml of methylene chloride and one drop of pyridine and themixture was stirred for one after which 13 ml of chloroform were added.The mixture was stirred for 18 hours and was then poured into 100 ml ofsaturated sodium thiosulfate solution. The mixture stirred for 10minutes and was extracted with chloroform. The organic phase was washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness under reduced pressure to obtain 2.8 g of3,3-dimethoxy-5α,10α-epoxy-17β-ethynyl-Δ⁹(11) -estrene-17α-ol which wasused as is for the next step. The product contained a small amount ofthe 5β,10β-epoxy compound.

STEP C:3,3-dimethoxy-11β-[4-(N,N-dimethylamino)-phenyl]-17β-ethynyl-.DELTA.⁹-estrene-5α,17α-diol

A mixture of 2.8 g of the product of Step B, 56 ml of anhydroustetrahydrofuran and 80 mg of anhydrous copper chloride was stirred underan inert atmosphere at room temperature for 5 minutes and was thenplaced in an ice bath. 33 ml 0.95M 4-dimethylaminophenyl magnesiumbromide in tetrahydrofuran were added dropwise to the mixture which wasthen allowed to return to room temperature.

63 ml of 4-dimethylaminophenyl magnesium bromide were added to asuspension of 6.15 g of dimethylsulfide-copper complex in 30 ml ofanhydrous tetrahydrofuran while keeping the temperature below 28.5° C.and the mixture was stirred for 30 minutes. Then, the above solution wasadded dropwise thereto and the mixture was stirred at room temperaturefor 18 hours and was then poured into aqueous saturated chloridesolution. The mixture was stirred for 10 minutes and was extracted withchloroform. The organic phase was washed with water, dried andevaporated to dryness under reduced pressure. The residue waschromatographed over silica gel and was eluted with a 1-1 petroleumether-ethyl acetate mixture containing 0.5 ppm of triethylamine. The1.28 g of product was chromatographed over silica gel and was elutedwith the same mixture to obtain 0.84 g of3,3-dimethoxy-11β-[4-(N,N-dimethylamino)-phenyl]-17β-ethynyl-.DELTA.⁹-estrene-5α,17α-diol.

STEP D: 11β- [4-(N,N-dimethylamino)-phenyl)-17β-ethynyl-Δ⁴,9-estradiene-17α-ol-3-one

A mixture of 0.76 g of the product of Step C, 15 ml of methanol and 1.6ml of 2N hydrochloric acid was stirred for 90 minutes and was thenpoured into an aqueous saturated sodium bicarbonate solution. Themixture was extracted with chloroform and the organic phase was driedand evaporated to dryness under reduced pressure. The 0.76 g of residuewas chromatographed over silica gel and was eluted with a 1-1petroleumether-ethyl acetate mixture and then with a 3-1 ether-petroleumether mixture to obtain 0.435 g of11β-[4-(N,N-dimethylamino)-phenyl]-17β-ethynyl-Δ⁴,9-estradiene-17α-ol-3-one which after crystallization from isopropylether melted at 142° C. and had a specific rotation of [α]_(D) ²⁰=+235.5°±4.5° (c=0.45% in chloroform).

EXAMPLE 22 11β-[4-(N,N-dimethylamino)-phenyl]-17α-phenyl-Δ⁴,9-estradiene-17β-ol-3-one STEP A: 3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-Δ⁹(11) -estrene 17-one

2 drops of pyridine were added to a mixture of 11.18 g of3,3-[1,2-ethanediyl-bisoxy]-Δ⁵(10),9(11) -estradiene-17-one and 56 ml ofmethylene chloride and 4.3 ml of hexafluoroacetone sesquihydrate wereadded to the mixture at 0° C.1.6 ml of 85% oxygenated water were addedto the mixture and the mixture was stirred under an inert atmosphere at0° C. for 23 hours and was poured into a mixture of 200 g of ice and 200ml of 0.5M sodium thiosulfate solution. The mixture was stirred for 30minutes and was extracted with methylene chloride containing a trace ofpyridine. The organic phase was washed with water, dried and evaporatedto dryness to obtain 11.4 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-Δ⁹(11) -estrene-17-one whichwas used as is for the next step.

STEP B:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-.DELTA.⁹-estrene-5α-ol-17-one

A mixture of 200 g of 4-dimethylamino benzene bromide in 950 ml ofanhydrous tetrahydrofuran was added over 2 1/2 hours at 35° C. ±5° C. toa mixture of 29 g of magnesium turnings and 50 ml of anhydroustetrahydrofuran under an inert atmosphere to obtain a solution of 0.8Mof magnesium.

284 ml of the said magnesium solution were added dropwise over 75minutes at 0 to 5° C. under an inert atmosphere to a mixture of 25 g ofthe product of Step A, 500 ml of anhydrous tetrahydrofuran and 0.757 gof copper chloride and the mixture was stirred for 15 minutes and pouredinto aqueous saturated ammonium chloride solution. The mixture wasextracted with ethyl acetate and the organic phase was washed withaqueous saturated ammonium chloride solution and with aqueous saturatedsodium chloride solution, dried and evaporated to dryness under reducedpressure. The 46 g of residue were chromatographed over silica gel andwere eluted with a 1-1 petroleum ether-ethyl acetate mixture containing1 ppm of triethylamine to obtain 17.76 g of product melting at 178° C.The impure fractions were subjected again to chromatography over silicagel and were eluted with an 8-2 petroleum ether-acetone mixturecontaining 1 ppm of triethylamine to obtain another 6.35 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4 (N,N-dimethylamino)-phenyl]Δ⁹-estrene 5α-ol-17-one melting at 176° C. which was used as is for thenext step.

STEP C:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-phenyl-Δ⁹-estrene-5α,17β-diol

A solution of 4.51 g of the product of Step B in 45.1 ml of anhydroustetrahydrofuran was added over 30 minutes at 25° C. to a solution of33.3 ml of phenyllithium (1.5 moles) and the mixture was stirred for 4hours at room temperature and was then poured into aqueous saturatedammonium chloride solution. The mixture was extracted with ether and theorganic phase was washed with aqueous saturate sodium chloride solution,dried and evaporated to dryness. The 5.6 g of residue werechromatographed over silica gel and were eluted with a 9-1 methylenechloride-acetone mixture containing of triethylamine to obtain 1.16 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.beta.-phenyl-Δ⁹-estrene-5α,17β-diol which after crystallization from an isopropylether-methylene chloride mixture melted at 240° C. had a specificrotation of [α]_(D) ²⁰ =+53°±2.5° (c=0.5in CHCl₃).

STEP D: 11β[4-(N,N-dimethylamino )-phenyl]-17α-phenyl-Δ⁴,9-estradiene-17β-ol-3-one

3 ml of 2N hydrochloric acid were added under an inert atmosphere at 0to 5° C. to a mixture of 1.5 g of the product of Step C in 45 ml. ofmethanol and the mixture was stirred at 0 to 5° C. for one hour. Then,90 ml of ether and 90 ml of an aqueous 0.25M of sodium bicarbonatesolution ere added to the mixture and the mixture was stirred for 5minutes. The decanted aqueous phase was extracted with ether and theorganic phase was washed with aqueous saturated sodium chloridesolution, dried and evaporated to dryness. The 1.3 g of residue werechromatographed over silica gel and were eluted with a 1-1 petroleumether ether mixture to obtain 0.93 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-phenylΔ⁴,9-estradiene-17β-ol-3-one which after crystallization from methylenechloride-isopropyl ether melted at 226° C. and had a specific rotationof [α]_(D) ²⁰ =+151.5° (c=0.4% in chloroform).

EXAMPLE 2311β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-.DELTA.⁴,9,23cholatriene 20-yn-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17αΔ⁹,23-choladiene-20-yn-5α,17β-diol

0.61 ml of 2-methyl-1-buten-3-yne were added under an inert atmosphereto a mixture of 4.5 g of potassium tert.-butylate in 90 ml of anhydroustetrahydrofuran and the mixture was stirred for 15 minutes at -10° C. Asolution of 4.5 g of the product of Step B of Example 22 in 45 ml ofanhydrous tetrahydrofuran was added over 15 minutes to the reactionmixture and the mixture was stirred at -10° C. for 30 minutes and thenfor 4 hours at 5° C. The mixture was poured into 500 ml of aqueoussaturated solution of ammonium chloride and the mixture was extractedwith ethyl acetate. The organic phase was washed with aqueous saturatedsodium chloride solution, dried and evaporated to dryness to obtain 5.56g of raw3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-Δ⁹,23-choladiene-20-yn-5α,17β-diol melting at 205° C. which was used as isfor the next step. The raw product was chromatographed over silica geland was eluted with a 9-1 methylene chloride-ethyl acetate containing 1part per 1000 of triethylamine and crystallized from ethyl acetate toobtain the product melting at 215° C.

STEP B:11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-.DELTA.⁴,9,23-cholatriene-20-yne-17β-ol-3-one

A mixture of 5 g of the product of Step A, 300 ml of methanol and 10 mlof 2N hydrochloric acid was stirred under an inert atmosphere for 15minutes at 20° C. and then 300 ml of methylene chloride and then 300 mlof aqueous 0.25M sodium bicarbonate solution were added thereto. Themixture was stirred for 10 minutes and the decanted aqueous phase wasextracted with methylene chloride. The organic phase was washed withwater, dried and evaporated to dryness. The 4.5 g of residue werechromatographed over silica gel and were eluted with a 1-1 petroleumether-ethyl acetate mixture to obtain after crystallization fromdiisopropyl oxide 2.01 g of11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-.DELTA.⁴,9,23-cholatriene-20-yne-17β-ol-3-one melting at 185° C. and having aspecific rotation of [α]_(D) ²⁰ =+88.5°±1.5° (c=1% in CHCl₃).

EXAMPLE 24 11β-[4-(N,N-dimethylamino)-phenyl]-17β-methoxy-23-methyl-19,21-dinor-17α-Δ⁴,9,23 -cholatriene-20-yne-3-one

10.61 ml of 2-methyl-1-buten-3-yne were added dropwise at -10° C. to asuspension of 4.5 g of potassium tert.-butylate in 90 ml of anhydroustetrahydrofuran under an inert atmosphere and the mixture was stirred at-10° C. for 15 minutes. Then, a mixture of 4.5 g of the product of StepB of Example 22 in 45 ml of anhydrous tetrahydrofuran was added over 15minutes (to the mixture which was then stirred at -10° C. for 30minutes) and at 0° to 5° C. for 4 hours. 7.5 ml of methyl iodide wereadded to the mixture which was then stirred in an ice bath for 30minutes and then poured into 500 ml of 0.1 N hydrochloric acid. Themixture was stirred for 30 minutes at room temperature and was thenextracted with ethyl acetate. The organic phase was washed with aqueoussaturated sodium bicarbonate solution, then with aqueous saturatedsodium chloride solution, dried and evaporated to dryness. The residuewas chromatographed over silica gel and was eluted with a 95-5 methylenechloride-ethyl acetate mixture to obtain 2.7 g of11β-[4-(N,N-dimethylamino)-phenyl]-178-methoxy-23-methyl-19,21-dinor-17α-Δ⁴,9,23-cholatriene-20-yne-3-one which after crystallization from methanolmelted at 105° C.

EXAMPLE 2511β[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ.sup.4,9-pregnadiene-20-yne 17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]118-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol

A solution of 7 ml of trichloroethylene in 28 ml of anhydrous ether wasadded with stirring under an inert atmosphere at 0 to 5° C. to a mixtureof 77.5 ml of 1M butyllithium in hexane and 310 ml of anhydrous etherand the mixture was stirred for one hour while the temperature rose to20° C. A solution of 7 g of Step B of Example 22 in 70 ml oftetrahydrofuran was added to the resulting mixture dropwise over 30minutes at 0 to 5° C. and the mixture was stirred at 0 to 5° C. for 30minutes after which the temperature was allowed to rise to 20° C. andwas slowly poured into an aqueous saturated ammonium chloride solutionand the decanted aqueous phase was extracted with methylene chloride.The organic phase was washed with water, dried and evaporated to drynessto obtain 8.5 g of raw product melting at 220° C. The latter was addedto 42.5 m of diisopropyl oxide and the mixture was stirred for 30minutes and vacuum filtered to obtain 6.38 g of product melting at 230°C. The latter was chromatographed over silica gel and as eluted with a7-3 benzene-ethyl acetate mixture containing 1 ppm of triethylamine. Theproduct was dissolved in methylene chloride and was precipitated byaddition of diisopropyl oxide to obtain 3,3-[1,2-ethanediyl-bisoxy]-11β-[4 (N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol melting at 240° C. and having a specificrotation of [α]_(D) ²⁰ =-83.5°±1.5° (c=1% in CHCl₃).

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]21-chloro-19-nor-17α-Δ.sup.4,9-pregnadiene-20-yne-17β-ol-3-one

15 ml of 2N hydrochloric acid were added under an inert atmosphere to amixture of 6.38 g of the product of Step A in 191.4 ml of 95% ethanoland after stirring the mixture for one hour, 300 ml of methylenechloride and then 200 ml of aqueous 0.25 mm sodium bicarbonate solutionwere added thereto. The decanted aqueous phase was extracted withmethylene chloride and the organic phase was washed with water, driedand evaporated to dryness under reduced pressure. The 6 g of residuewere chromatographed over silica gel and were eluted with a 7-3benzene-ethyl acetate mixture to obtain 3.95 g of11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one which after crystallization from ethylacetate melted at 240° C. and had a specific rotation of [α]_(D) ²⁰=+111°±2° (c=1% in chloroform).

EXAMPLE 26 N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴,9-pregnadiene -20-yne-17β-ol-3-one

A mixture of 0.54 g of 85% M-chloroperbenzoic acid in 10.8 ml ofmethylene chloride was added under an inert atmosphere at 0 to 5° C. toa mixture of 1.2 g of the product of Example 25 in 24 ml of methylenechloride and the mixture was stirred for one hour at 0 to 5° C. and wasthen poured into aqueous 0.2N sodium thiosulfate solution. The mixturewas extracted with methylene chloride and the organic phase was washedwith aqueous saturated sodium bicarbonate solution, with water, driedand evaporated to dryness. The 1.3 g of residue was chromatographed oversilica gel and was eluted with a 7-3 methylene chloride-methanol mixtureto obtain 1.15 g of N-oxide of 11β-[4-(N,N-dimethylamino)-phenyl]-21chloro-19-nor-17α-Δ⁴,9 -pregnadiene-20-yne-17β-ol-3-one with a specificrotation of [α]_(D) ²⁰ =+47.5°±1.5° (c=0.7% in chloroform).

EXAMPLE 27 N-oxide of 11β-[4-(N,N-dimethylamino)-phenyl]-9α,10β-epoxy-21-chloro-19-nor-17α-Δ⁴ -pregnene-20-yne-17β-ol-3-one

A mixture of 1.17 g of 85% m-chloroperbenzoic acid in 23.4 ml ofmethylene chloride was added over 15 minutes at 0 to 5° C. to a solutionof 1.18 g of the product of Example 25 in 23.6 ml of methylene chlorideand the mixture was stirred for 2 hours at 20° C. after which another1.17 g of 85% M-chloroperbenzoic acid were added. The mixture wasstirred for one hour and was poured into a solution of aqueous 0.2 Nsodium thiosulfate. The mixture was extracted with methylene chlorideand the organic phase was washed with aqueous saturated sodiumbicarbonate solution and then with water, dried and evaporated todryness to obtain 1.14 g of residue melting at 220°C. The residue waschromatographed over silica gel and was eluted with an 8-2 methylenechloride-methanol mixture to obtain 1 g of N-oxide11β-[(4-(N,N-dimethylamino)-phenyl 9α,10α-epoxy-21-chloro-19-nor-17α-Δ⁴-pregnene-20-yne-17β-ol 3-one melting at 270° C. and having a specificrotation of [α]_(D) ²⁰ =+39.5°±2.5° (c=0.5% in chloroform).

EXAMPLE 289α,10α-epoxy-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴-pregnene-20-yne-17β-ol-3-one

0.34 g of triphenylphosphine were added under an inert atmosphere to amixture of 0.63 g of the product of Example 27 in 6.3 ml of acetic acidand the mixture was stirred at room temperature for 45 minutes and wasthen poured into water. The mixture was extracted with methylenechloride and the organic phase was washed with water, dried andevaporated to dryness. The 0.9 g of residue was chromatographed oversilica gel and was eluted with a 1-1 petroleum ether-ethyl acetatemixture. The product was crystallized from a methylenechloride-isopropyl ether mixture to obtain 0.346 g of 9α,10α-epoxy11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴-pregnene-20-yne-17β-ol-3-one melting at 265° C. and having a specificrotation of [α]_(D) ²⁰ =+45°±2° (c=0.8% in chloroform).

EXAMPLE 2911β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ.sup.4,9-pregnadiene-20-yne-17β-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17 diol

A mixture of 4.17 g of potassium tert.-butylate in 83 ml of anhydroustetrahydroforan was stirred under an inert atmosphere for 10 minutes andthen 4.5 ml of phenyl acetylene were added dropwise at -10° C. Thesuspension was stirred for 5 minutes and then a solution of 4.17 g ofthe product of Step B of Example 22 in 41 ml of anhydroustetrahydrofuran was added thereto dropwise at -10° C. Then, thetemperature rose to 0° C. and held there for one hour and was thenpoured into an aqueous saturated ammonium chloride solution. The mixturewas extracted with ether and the organic phase was washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness. The4.7 g of residue were chromatographed over silica gel and eluted with a95-5 methylene chloride-acetone mixture to obtain 3.71 of3,3-[1,2-ethanediyl-bisoxy]-11β-[4,(N,N-dimethylamino-phenyl]-21-phenyl-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol melting at 168° C. and having a specificrotation of [α]_(D) ²⁰ =-119.5°±2° (c=1% in chloroform).

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one

6.3 ml of 2N hydrochloric acid were added to a solution of 3.49 g of theproduct of Step A in 68 ml of methanol and the mixture was stirred for30 minutes and was poured into a mixture of 180 ml of ether and 90 ml ofaqueous 0.25M sodium bicarbonate solution. The mixture was stirred for 5minutes and the decanted aqueous phase was extracted with ether. Theorganic phase was washed with aqueous 0.25M sodium bicarbonate solution,then with aqueous sodium chloride, dried and evaporated to dryness. The4.35 g of residue were chromatographed over silica gel and eluted with a95-5 methylene chloride-acetone mixture to obtain 2.13 g of11β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ⁴,9-pregnadiene 20-yne-17β-ol-3-one which after crystallization fromisopropyl ether had a specific rotation of [α]_(D) ²⁰ =+22.5°±1° (c=1%in chloroform).

EXAMPLE 30 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(propa-1,2-dienyl)-Δ⁴,9 -estradiene-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17α-(propa-1,2-dienyl)-Δ⁹estrene-5α,17β-diol and3,3-[1,2-ethanediyl-bisoxy]-11α-[4-(N,N-dimethylamino)phenyl-17.alpha.-(prop-2-ynyl)-Δ⁹-estrene-5α,17β-diol

Allene was bubbled into 50 ml of anhydrous tetrahydrofuran at 0 to 5° C.until 2,1 g were absorbed and 23.9 ml of a solution of a 1.3M ofbutyllithium in hexane were added thereto over 15 minutes at -70° C. Themixture was stirred at -70° C. 15 minutes and then a solution of 3.5 gof the product of Step B of Example 22 in 35 ml of anhydroustetrahydrofuran were added thereto at -70° C. over 25 minutes. Themixture was stirred at -70° C. for one hour and was poured slowly intoan iced aqueous saturated ammonium chloride solution. The mixture wasextracted with ether and the organic phase was washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness. The3.4 g of residue were chromatographed over silica gel and eluted with a1-1 petroleum ether-ethyl acetate mixture containing 1 ppm oftriethylamine to obtain 1.73 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(propa-1,2-dienyl)-Δ⁹-estrene-5α, 17β- diol melting at 178° C. and having a specific rotationof [α]_(D) ²⁰ =-32°±2° (c=0.7% in chloroform) and 1.5 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-ynyl)-Δ⁹ -estrene-5α,17β-diol melting at 150° C. and havinga specific rotation of [α]_(D) ²⁰ =-15°±2° (c=0.9% in chloroform).

STEP B:11β-[4-(N,N-dimethylamino)-phenyl]-17α-(propa-1,2-dienyl)-.DELTA.⁴,9-estradiene-17β-ol-3 one

A mixture of 1.73 g of the 17α-(propa-1,2-dienyl)isomer of Step A, 51.8ml of 95% ethanol and 3.5 ml of 2N hydrochloric acid was stirred underan inert atmosphere at 20° C. for one hour and then 50 ml of methylenechloride and 50 ml of aqueous 0.25M sodium bicarbonate solution wereadded thereto. The decanted aqueous phase was extracted with methylenechloride and the organic phase was washed with water, dried andevaporated to dryness. The 1.51 g of residue were dissolved in 10 ml ofhot methylene chloride and 15 ml of isopropyl ether were added to thesolution. The mixture was concentrated and allowed to stand to obtain1.23 g of product which were crystallized form a methylenechloride-isopropyl ether mixture to obtain 1.11 g of11β[4-(N,N-dimethylamino)-phenyl]-17α-(propa-1,2-dienyl)-.DELTA.⁴,9-estradiene 17β-ol 3-one melting at 228° C. and having a specificrotation of [α]_(D) ²⁰ =+139.5°±3° (c=0.8% in chloroform).

EXAMPLE 3111β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

A mixture of 0.94 g of the 17α-(prop-2-ynyl)-isomer of Step A of Example30 , 28.2 ml of 95% ethanol and 2 ml of 2N hydrochloric acid was stirredat 20° C. for one hour and then 50 ml of methylene chloride and 50 ml ofan aqueous 0.25M sodium bicarbonate solution were added thereto. Thestirred for 5 minutes and tn decanted aqueous phase was with methylenechloride. The organic phase was washed with water, dried and evaporatedto dryness and the residue was chromatographed over silica gel. Elutionwith a 1-1 petroleum ether-ethyl acetate mixture yielded 0.42 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-[prop- 2-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =+143°±3° (c=0.8% in chloroform).

EXAMPLE 32 11β-[4-(N,N-dimethylamino)-phenyl]17α-ethynyl-Δ⁴,9-estradiene 17β-ol-3-one STEP A:3,3-[1,2-ethenediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.beta.-cyano-17α-trimethylsilyloxy-Δ⁹-estrene-5α-ol

A solution of 18 mmoles of [4-(N,N-dimethylamino)phenyl]-magnesiumbromide in anhydrous tetrahydrofuran was added under an inert atmosphereto a suspension of 2.05 g of dimethylsulfide-copper bromide complex in10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 30minutes after which 20 ml of anhydrous triethylamine were added thereto.to. A solution of 0.95 g of 3,3[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17β-cyano-17α-trimethylsilyloxy-Δ⁹(11)-estrene in anhydrous tetrahydrofuran were added to the mixture whichwas then stirred for 15 hours at room temperature and poured 50 ml ofaqueous saturated ammonium chloride solution. The decanted aqueous phasewas extracted with ether and the organic phase was washed with water,dried and evaporated to dryness. The residue was chromatographed oversilica gel and was eluted with an 8-2 benzene-ethyl acetate mixture toobtain 1.1 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.beta.-cyano-trimethylsilyloxy-Δ⁹-estrene-5α-ol which after crystallization from isopropyl ether meltedat 247° C. and had specific rotation of [α]_(D) ²⁰ =-12.5° (c=1% inchloroform).

STEP B:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethynyl-⁹-estrene-5α,17β-diol

1 g of the acetylide complex of lithium ethylene-diamine was added to amixture of 0.8 g of the product of Step A in 8 ml of ethylenediamine ahdthe mixture was stirred under an inert atmosphere at ˜50° C. for 90minutes. The mixture was cooled to 20° C. and was poured into aqueousammonium chloride solution. The mixture was extracted with ether andmethylene chloride and the organic phase was dried and evaporated todryness. The residue was chromatographed over silica gel and was elutedwith a 7-3 benzene-ethyl acetate mixture. The product was crystallizedfrom isopropyl ether to obtain 0.43 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁹ -estrene-5α,17β-diol meltingat 199° C. and having a specific rotation of [α]_(D) ²⁰ =-43 °±1.5°(c=1% in chloroform).

STEP C: 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ.sup. 4,9-estradiene-17β-ol-3-one

1 ml of 2N hydrochloric acid was added to a solution of 0.25 g of theproduct of Step B in 6 ml of methanol and the mixture was stirred at 20°C. for 40 minutes and then was poured into water containing 2.5 ml of Nsodium hydroxide. The mixture was extracted with ether and the organicphase was dried and evaporated to dryness. The residue waschromatographed over silica gel and was eluted with a 7-3 benzene-ethylacetate mixture to obtain 0.25 of11β-[4-(N,N-dimethylamino)phenyl]-17α-ethynyl-Δ⁴,9-estradiene-17β-ol-3-one.

Analysis: C₂₈ H₃₃ NO₂ ; molecular weight=415.54, Calculated: % C 80.92,% H 8.00, % N 3.37, Found: 80.7, 8.1, 3.1.

EXAMPLE 33 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9-estradiene 17β-ol-3-one STEP A;3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethynyl-Δ⁹-estrene-5α,17β-diol 12.25 g of the acetylide complex of lithiumethylene-diamine were added under an inert atmosphere to a solution of 6g of the product of Step B of Example 22 in 180 ml of tetrahydrofuranand the mixture was stirred at 55° C. for 4 hours and as then cooled andpoured into 600 ml of an iced aqueous saturated ammonium chloridesolution. The mixture was extracted with ether and the organic phase waswashed with aqueous saturated sodium chloride solution, dried andevaporated to dryness. The residue was chromatographed over silica geland with a 7-3 benzene-ethyl acetate mixture containing 1 ppm oftriethylamine. The 4.5 g of product was from a methylenechloride-diisopropyl oxide mixture to obtain3,3[1,2-ethanediyl-bisoxy]-11β-14-(N,N-dimethylamino)-phenyl]-17.alpha.-ethynyl-Δ⁹-estrene-5α,17β-diol melting at 202° C. and having a specific rotationof [α]_(D) ²⁰ =-47.5°±1.5° (c=1% in chloroform). STEP B: 11β-[4(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9 -estradiene-17β-ol-3-one

5 ml of 2N hydrochloric acid were added to a suspension of 2 g of theproduct of Step A in 50 ml of 95% ethanol and the mixture was stirred at20° C. for one hour. 100 ml of ether and then 100 ml of aqueous. 0.25Msodium bicarbonate solution were added to the mixture and the decantedaqueous phase was extracted with ether. The organic phase was washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness and the residue was chromatographed over silica gel. Elutionwith a 6-4 petroleum ether-ethyl acetate mixture yielded 1.52 g of11β[4-(N,N-dimethylamino)-phenyl]17-ethynyl-Δ4,9-estradiene-17.beta.-ol-3-onewhich after crystallization from diisopropyl oxide melted at 172° C. andhad a specific rotation of [α]_(D) ²⁰ =+182°±2.5° (c=1% in chloroform).

EXAMPLE 34 11β-[3-(N,N-dimethylamino)-phenyl]-17α-(prop-1 -ynyl)-Δ⁴,9-estradiene-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A mixture of 10 g of m-bromo-dimethylaniline in 45 ml of anhydroustetrahydrofuran was added under an inert atmosphere over 45 minutes to amixture of 1.46 g of magnesium and 5 ml of anhydrous tetrahydrofuran andthe reaction was started by addition of dibromomethane. The mixture wasstirred for one hour to obtain a solution of 0.95M of magnesium and 42.2ml of the solution were added at 0 to 5° C. over 30 minutes under aninert atmosphere to a mixture of 3.7 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol, 74 ml of anhydrous tetrahydrofuran and 99 mg of copperchloride and the mixture was stirre-d for 30 minutes at 0° to 5° C. andwas poured into an aqueous saturated ammonium chloride solution. Themixture was extracted with ether and the organic phase was washed withaqueous saturated sodium chloride solution, dried and evaporated todryness. The was chromatographed over silica gel and eluted with a 9-1methylene chloride-acetone mixture containing 1 part per 1000triethylamine to obtain 3.5g of3,3-[1,2-ethanediyl-bisoxy]11β-[3-(N,N-dimethylamino)-phenyl]-17α-(prop-1 ynyl)-Δ⁹ -estrene-5α, 17β-diol melting at 262° C. and having aspecific rotation of [α]_(D) ²⁰ =-64°±1.5° (c=1% in chloroform) and 0.66g of the corresponding 5β-ol isomer melting at 210° C. and having aspecific rotation of [α]_(D) ²⁰ =+32.5°±1° (c=0.8% in chloroform).

STEP B: 11β-[3-(N,N-dimethylamino)-phenyl]-17α-(prop 1-ynyl-Δ⁴,9-estradiene-17β-ol-3-one

10 ml of 2N hydrochloric acid were added at 0 to 5° C. under an inertgas to a mixture of 3.3 g of the product of step A in 100 ml of methanoland the mixture was stirred at 0 to 5° C. for one hour. 200 ml ofdiethyl oxide and then 200 ml of aqueous 0.25M sodium bicarbonatesolution were added to the mixture which was then stirred for 5 minutes.The decanted aqueous phase was extracted with diethyloxide and theorganic phase was washed with aqueous saturated sodium chloridesolution, dried and evaporated to dryness. The 3 g of residue werechromatographed over silica gel and eluted with a 7-3 benzene-ethylacetate mixture to obtain 1.43 g of amphorous11β-[3-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+43°±2.5° (c=1% in CHCl₃).

EXAMPLE 35 N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

A solution of 0.71 g of 85% m-chloroperbenzoic acid in 14.2 ml ofmethylene chloride was added over 10 minutes at 0° to 5° C. to a mixtureof 1.5 g of the product of Example 19 in 30 ml of methylene chloride andthe mixture was stirred for one hour at 0° to 5° C. and was poured into100 ml of an aqueous 0.2N sodium thiosulfate solution. The decantedaqueous phase was extracted with methylene chloride and the organicphase was washed with aqueous 0.5M sodium bicarbonate solution, driedand evaporated to dryness. The residue was dissolved in 20 ml ofmethylene chloride and 20 ml of diisopropyl oxide were added thereto.Crystallization was induced and the mixture stood for a while and wasvacuum filtered. The crystals were dried to obtain 1.4 g of N-oxide of11β- [4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one melting at 210° C. and having a specificrotation of [α]_(D) ²⁰ =73.5°±2° (c=1% in chloroform).

EXAMPLE 36 11β-[4-(N,N-dimethylamino)-phenyl]-Δ⁴,9-estradiene-17β-ol-3-one

106 mg of sodium borohydride were added to a solution of 1 g of theproduct of Step B of Example 22 in 20 ml of tetrahydrofuran containing10% water and the mixture was stirred for one hour and poured into 200ml of water. The mixture was extracted with methylene chloride and theorganic phase was washed with aqueous saturated sodium chloridesolution, dried and evaporated to dryness to obtain 1.3 g of11-β[4-(N,N-dimethylamino)-phenyl]-Δ⁴,9 -estradiene-5α,17β-diol-3-one.0.63 g of the latter were added to a mixture of 12 ml of methanol and2.4 ml of 2N hydrochloric acid and the mixture was stirred at roomtemperature for 90 minutes and was poured into aqueous sodiumbicarbonate. The mixture was extracted with ether and the organic phasewas washed with aqueous rated sodium chloride solution, dried andevaporated to dryness. The residue was chromatographed over silica geland was eluted with a 6-4 petroleum ether-ethyl acetate mixture. Theresidue was triturated with petroleum ether and vacuum filtered toobtain 0.38 g of 11β-[4-(N,N-dimethylamino)-phenyl]-Δ⁴,9-estradiene-17β-ol-3-one melting at 130° C. and having a rotation of[α]_(D) ²⁰ =+277°±5° (c=0.5% in chloroform).

EXAMPLE 3711β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-enyl)-Δ.sup.4,9-estradien-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-enyl)-Δ⁹-estrene-5α,17β-diol

A solution of 3.5 g of the -product of Step B of Example 22 in 35 ml oftetrahydrofuran was added under an inert atmosphere at 20° C. over 15minutes to 55.5 ml of 0.7M allyl magnesium bromide in ether and themixture was stirred at 20° C. for one hour and was then poured into anaqueous saturated ammonium chloride solution. The mixture was extractedwith and the organic phase was washed with aqueous saturated sodiumchloride solution, dried and evaporated to dryness. The residue wasdissolved in 10 ml of methylene chloride and 15 ml of diisopropyl oxidewere added to the solution which was then concentrated and allowed tostand. The mixture was vacuum filtered and the crystals were rinsed withdiisopropyl oxide and dried to obtain 2.76 g of3,3-[1,2-ethanediyl-bisoxyl]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-enyl)-Δ⁹-estrene-5α,17β-diol melting at 198° C.

Analysis: C₃₁ H₄₃ NO₄ ; molecular weight=493.69, Calculated: % C 74.42,% H 8.78, % N 2.83, Found 74.0, 8.7, 2.9.

STEP B 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-enyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

4.5 ml of 2N hydrochloric acid were added to a suspension of 2.2 g ofthe product of Step A in 66 ml of methanol and the mixture was stirredat 20° C. for 30 minutes after which 132 ml of diethyl oxide and then132 ml of aqueous 0.25M sodium bicarbonate solution were added thereto.The aqueous phase was extracted with diethyl oxide and the organic phasewas washed with aqueous saturated sodium chloride solution, dried andevaporated to dryness. The residue was chromatographed over silica geland was eluted with a 7-3 benzene-ethyl acetate mixture. The product wastaken up in a mixture of 15 ml of diisopropyl oxide and 7.5 ml ofmethylene chloride and the solution was concentrated and allowed tostand. The mixture was vacuum filtered and the crystals were rinsed withdiisopropyl oxide and dried to obtain 1.365 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-enyl)-Δ.sup.4,9-estradiene-17β-ol-3-one melting at 182° C. and having a specificrotation of [α]_(D).sup. 20 =+206.5°±3° (c=1% in chloroform).

EXAMPLE 3811β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17α-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 42.8 g of 4-(N,N-dimethylaminomethyl)bromobenzene in 190ml of anhydrous tetrahydrofuran was added over 90 minutes under an inertatmosphere at 45° to 50° C. to mixture of 5.5 g of magnesium in 10 ml ofanhydrous tetrahydrofuran and the reaction was induced withdibromoethane addition. The mixture was stirred for one hour to obtainan 0.85M magnesium solution and 127 ml of the said solution were addedunder an inert atmosphere at 0° to 5° C. over one hour to a mixture of10 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol, 200 ml of anhydrous tetrahydrofuran and 0.27 g ofcopper chloride. The mixture was stirred for 15 minutes and was pouredinto an aqueous saturated ammonium chloride solution. The mixture wasextracted with ether and the organic phase was washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness. Theresidue was chromatographed over silica gel and was eluted with a 9-1methylene chloride-methanol mixture containing 1 part per 1000 oftriethylamine to obtain 10.1 g of product. The latter was dissolved inmethylene chloride and a few drops of methanol and then diisopropyloxide were added thereto. The mixture was concentrated, allowed to standfor 6 hours and was vacuum filtered to obtain 7.37 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol melting at 186° C. and having a specific rotationof [α]_(D) ²⁰ =-63°±2.5° (c=0.5% in chloroform).

STEP B:11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

A mixture of 15 ml of 2N hydrochloric acid, 7.37 g of the product ofStep A and 147.4 ml of methanol was stirred at 20° C. for one hour andthen 300 ml of diethyl oxide and 300 ml aqueous 0.25M sodium bicarbonatesolution were added thereto. The decanted aqueous phase was extractedwith diethyl oxide and the organic phase was washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness. Theproduct was dissolved in a mixture of diisopropyl oxide and methylenechloride and the solution was concentrated and allowed to stand. Themixture was vacuum filtered and crystals were dried to obtain 3.74 g of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one melting at 190° C. and having a specificrotation of [α]_(D) ²⁰ =+84.5°±2° (c=0.8% in chloroform).

EXAMPLE 39 11β-[4-pyrrolidinyl-phenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-(4-pyrrolidinylphenyl-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 34 g of 4-pyrrolidinyl-bromobenzene in 140 ml of anhydroustetrahydrofuran was added over one hour an inert atmosphere at 45°-50°C. to a mixture of 4 g of magnesium and 10 ml of anhydroustetrahydrofuran and the reaction was started by addition ofdibromoethane to obtain a 1M magnesium solution. 86.4 ml of the saidsolution were added over 90 minutes at 0° to 5° C. under an inertatmosphere to a mixture of 8 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol in 160 ml of anhydrous tetrahydrofuran and 216 mg ofcopper chloride and the mixture was stirred for one hour and was pouredinto an aqueous saturated ammonium chloride solution. The mixture wasextracted with diethyl oxide and the organic phase was washed withaqueous saturated ammonium chloride solution, aqueous saturated sodiumchloride solution, dried and evaporated to dryness. The residue waschromatographed over silica gel and was eluted with a 95-5 methylenechloride-acetone mixture containing part per 1000 of triethylamine toobtain 8.3 g of3,3-[1,2-ethanediylbisoxy]-11β-(4-pyrrolidinyl-phenyl)-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol which after crystallization from a methylenechloride-isopropyl ether mixture melted at 185° C. and had a specificrotation of [α]_(D) ²⁰ =-67°±1.5° (c=1% chloroform).

STEP B: 11β-(4-pyrrolidinyl-phenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

A mixture of 13 ml of 2N hydrochloric acid, 6.4 g of the product of StepA and 128 ml of methanol was stirred at 20° C. for one hour and then 256ml of diethyl oxide and 256 ml of aqueous 0.25M sodium bicarbondatesolution were added thereto. The decanted aqueous phase was extractedwith diethyl oxide and the organic phase was washed with aqueous 0.25Msodium bicarbonate solution, with aqueous saturated sodium chloridesolution, dried and evaporated to dryness. The residue waschromatographed over silica gel and was eluted with a 1-1 petroleumether-ethyl acetate mixture to obtain 5.25 g of11β-(4-pyrrolidinyl-phenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one which after crystallization from a methylenechloride-dissopropyl oxide mixture melted at 190° C. and had a specificrotation of [α]_(D) ²⁰ =+120°±2.5° (c=1.2% in chloroform).

EXAMPLE 40 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethenyl-Δ⁴,9-estradiene-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethenyl-66⁹ -estrene-5α,17β-diol

A current of hydrogen was passed for one hour through a mixture of 3 gof the product of Step B of Example 32, 60 ml of anhydrous pyridine and0.6 g of 5% palladized calcium carbonate at room temperature and themixture was then vacuum filtered. The filtrate was evaporated to drynessand the residue was taken up in toluene. The solution was evaporated todryness to obtain 2.94 g of3,3-[1,2-ethanediyl-bisoxyl]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethenyl-Δ⁹-estrene-5α,17β-diol melting at 181° C. which was used as is for thenext step. A sample after crystallization from a mixture of methylenechloride-diisopropyl oxide melted at 182° C. and had a specific rotationof [α]_(D) ²⁰ =-6.5°±2° (c=0.7% in chloroform).

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethenyl-Δ⁴,9-estradiene-17β-ol-3-one

A mixture of 6.2 ml of 2N hydrochloric acid, 2.94 g of the product ofStep A and 60 ml of methanol was stirred at 20° C. for one hour and then120 ml of ether and 120 ml of aqueous 0.25M sodium bicarbonate solutionwere added there to. The mixture was stirred for 10 minutes and thedecanted aqueous phase was extracted with ether. The organic phase waswashed with aqueous 0.25M sodium bicarbonate solution, aqueous saturatedsodium chloride solution, dried and evaporated to dryness. The 2.65 g ofresidue were chromatographed over silica gel and eluted with a 7-3benzene-ethyl acetate mixture. The product was crystallized from adiisopropyl oxide-methylene chloride mixture to obtain 1.51 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethenyl-Δ⁴,9-estradiene-17β-ol-3-one melting at 150° C. and having a specificrotation of [α]_(D) ²⁰ =+243°±3° (c=0.8% in chloroform).

EXAMPLE 41 11β-[4-(N,N-diethylamino)-phenyl-]17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one STEP A: 4-(N,N-diethylamino)-bromobenzene

93 g of bromine were added dropwise to a solution of 86 g ofN,N-diethylaniline in 400 ml of acetic acid and the mixture was pouredinto an ice-water mixture. The mixture was extracted with methylenechloride and the organic phase was washed with aqueous sodiumbicarbonate solution, dried and evaporated to dryness to obtain 125 g of4-(N,N-diethylamino)-bromobenzene boiling at 97° C. at 0.6 mm Hg.

STEP B:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-diethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 34.2 g of 4-(N,N-diethylamino)-bromobenzene in 110 ml oftetrahydrofuran was added at 35° C. under an inert atmosphere to amixture of 3.9 g of magnesium and 10 ml of tetrahydrofuran to obtain a1M magnesium solution and 80 ml of the said solution was slowly addedwith stirring at 0° to 5° C. under an inert atmosphere to a solution of7.4 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol, 150 ml of anhydrous tetrahydrofuran and 0.25 g ofcopper chloride. The mixture was stirred at 20° C. for 17 hours and wasthen poured into an aqueous ammonium chloride solution. The mixture wasextracted with ether and the organic phase was washed with aqueoussodium bicarbonate solution, dried and evaporated to dryness. Theresidue was empasted with petroleum ether and treated with activatedcarbon in ether. The product was crystallized from isopropyl ether toobtain 4 g of3,3-[1,2-ethanediyl-bisoxyl]-11β-[4-(N,N-diethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol with a specific rotation of [α]_(D) ²⁰ =-61°±2.5°(c=0.7% in CHCl₃).

STEP C: 11β-[4-(N,N-diethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

A mixture of 8 ml of 2N hydrochloric acid, 3.12 g of the product of StepB and 45 ml of methanol was stirred at 20° C. under an inert atmospherefor 45 minutes and was then poured into water. The mixture wasneutralized by addition of 2N sodium hydroxide solution and wasextracted with methylene chloride. The organic phase was dried andevaporated to dryness and the residue was chromatographed over silicagel. Elution with a 1-1 benzene-ethyl acetate mixture yielded 1.34 g of11β-[4-(N,N-diethylamino)-phenyl]-17α-(prop-1-yny)-Δ.sup.4,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+144.5°±3° (c=0.8% in chloroform).

Analysis: C₃₁ H₃₉ NO₂ ; molecular weight=457.63, Calculated: % C 81.36,% H 8.59, % N 3.06, Found: 81.7, 8.8, 2.09.

EXAMPLE 4211β-[4-(N-methyl-N-3-methylbutylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one STEP A: N-methyl-N-(3-methylbutyl)-aniline

121 g of isoamyl bromide were added dropwise to a mixture of 86 g ofN-methyl-aniline, 500 ml of anhydrous benzene and 81 g of anhydroustriethylamine and the mixture was refluxed for 100 hours and wasfiltered. The filtrate was washed with water, dried and evaporated todryness. The residue was distilled to obtain 90 g ofN-methyl-N-(3-methylbutyl)-aniline boiling at 132° C. at 18 mm Hg.

STEP B: N-methyl-N-(3-methylbutyl)-4-bromo-aniline

A solution of 58 g of bromine in 60 ml of acetic acid was added dropwiseat about 15° C. over one hour to a mixture the mixture was stirred at80° C. for 8 hours and was poured into iced water. The mixture wasextracted with methylene chloride and the organic phase was washed withaqueous sodium bicarbonate, with water, dried and evaporated to dryness.The residue was distilled to obtain 70 g of N-methylN-(3-methylbutyl)-4-bromo-aniline boiling at 119° C. at 0.5 mm Hg.

STEP C:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N-methyl-N-3-methylbutylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A few ml of a solution of the product of Step B in tetrahydrofuran wereadded under an inert atmosphere to a mixture of 4.12 g of magnesium and10 ml of tetrahydrofuran and reaction was started by addition of 0.2 mlof 1,2-dibromoethane. The rest of the solution of the product of Step Bin tetrahydrofuran (32.6 g in 90 ml) was added over 40 minutes to themixture and after the temperature returned to room temperature, themixture was stirred for one hour to an 0.9M magnesium solution. Amixture of 3.77 g of copper chloride, 8 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17α-ol and 90 ml anhydrous tetrahydrofuran was stirred under aninert atmosphere at 5° C. for 20 minutes and then 100 ml of themagnesium solution were added thereto. The mixture was poured intoaqueous ammonium chloride solution and was extracted with ethercontaining triethylamine and then with methylene chloride containingtriethylamine. The combined organic phases were washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness toobtain 31.2 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N-methyl-N-3-methylbutylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol which was used as is for the next step. A sample ofthe product was chromatographed over silica gel and was eluted with a96.5-4.5-0.5 methylene chloride-acetone-triethylamine mixture to obtainthe compound with a specific rotation of [α]_(D) ²⁰ =-59.5°±2.5° (c=0.7%in chloroform).

D:11β-[4-(N-methyl-N-(3-methyl-butyl)-amino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

A mixture of 52 ml of 2N hydrochloric acid, 26 g of the product of StepC and 200 ml of methanol was stirred for one hour and was then pouredinto aqueous sodium bicarbonate. The mixture was extracted with etherand then methylene chloride and the combined organic phases were washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness. The residue was chromatographed over silica gel and was elutedwith an 92-8 toluene-ethyl acetate mixture to obtain 3.23 g of11β-[4-(N-methyl-N (3-methyl-butyl)-amino)phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+125°±3.5° (c=0.6% in chloroform).

Analysis: C₃₃ H₄₃ NO₂ ; molecular weight=485.71, Calculated: % C 81.6, %H 8.92, % N 2.88, Found: 81.4, 9.0, 2.7.

EXAMPLE 4311β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one STEP A:4-(N,N-dimethylaminoethylthio)-bromobenzene

A solution of 23.5 g of chloroethyldimethylamine.HCl in 75 ml of ethanolwas added to 160 ml of sodium hydroxide solution formed by dissolving 20g of sodium hydroxide pastilles in 500 ml of ethanol. A solution of 30 gof 4-bromothiophenol in 100 ml of ethanol was added to 160 ml of thesaid sodium hydroxide solution and the first solution was added theretoover 2 minutes at 20° C. The mixture was refluxed for 3 hours and wasevaporated to dryness. Water was added to the residue and the mixturewas extracted with methylene chloride. The organic phase was washed withaqueous 0.1N sodium hydroxide solution, then with water, dried andevaporated to dryness. The residue was distilled to obtain 35.5 g of4-(N,N-dimethylaminoethylthio)-bromobenzene boiling at 110° C. at 0.1 mmHg.

STEP B:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 20 g of the product of Step A in 40 ml of anhydroustetrahydrofuran was added over 45 minutes under an inert atmosphere to amixture of 2 g of magnesium and 15 ml of tetrahydrofuran while thetemperature rose to 56° C. and the reaction was started by addition of1,2-dibromoethane. The mixture was returned to 20° C. and was stirred at20° C. for 45 minutes under an inert atmosphere to obtain a 1.05Mmagnesium solution.

1.730 g of copper chloride were added with stirring at -20° C. under aninert atmosphere to 38 ml of the said magnesium solution and the mixturewas stirred for 20 minutes. A solution of 5 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol in 50 ml of anhydrous tetrahydrofuran was added to themixture which was then stirred for 24 hours under an inert atmosphere at20° C. and was then poured into 600 ml of iced water containing 60 g ofammonium chloride. The decanted aqueous phase was extracted with diethyloxide containing triethylamine and the combined organic phase was washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness. The residue was chromatographed over silica gel and was elutedwith a 95-5 methylene chloride-acetone mixture to obtain 10.3 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-Δ⁹ -estrene-5α,17β-diol.

IR Spectrum: Absorption at 3600 cm⁻¹ (OH); at 2240 cm⁻¹ (C.tbd.C); at1705 and 1670 cm⁻¹ (CO and conjugated CO); at 1615 and 1490 cm⁻¹(aromatic bands).

STEP C:11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

A mixture of 20.6 ml of 2N hydrochloric acid, 10.3 g of the product ofStep B and 72 ml of methanol was stirred at 20° C. under an inertatmosphere for 25 minutes and was neutralized by addition of aqueoussaturated sodium bicarbonate solution. 200 ml of diethyl oxide wereadded to the mixture and the decanted aqueous phase was extracted withdiethyl oxide. The combined organic phases were washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness andthe residue was chromatographed over silica gel. Elution with a 9-1methylene chloride-methanol mixture yielded 3 g of11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17α-ol-3-one which after crystallization by empasting withdiisopropyl oxide melted at 145° C. and had a specific rotation of[α]_(D) ²⁰ =+125°±2° (c=1% in chloroform).

EXAMPLE 44 11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17α-Δ⁴,9 -pregnadiene-20-yne-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl19-nor-17α-Δ⁹ -pregnene-20yne-5α,17β-dial

A mixture of 13 ml of a 1.6M ethyl magnesium bromide tetrahydrofuran and13 ml of anhydrous tetrahydrofuran was stirred for 5 minutes at 0° to 5°C. and 3.4 ml of trimethylsilyl acetylene were added thereto dropwise.The temperature allowed to rise to 20° C. and the mixture was thenstirred or 20 minutes. Then, a solution of 1.12 g of the product of StepB of Example 22 in 10 ml of anhydrous tetrahydrofuran was added dropwiseto the mixture and the mixture was stirred at room temperature for 16hours and was poured into aqueous ammonium chloride solution. Themixture was stirred at room temperature for 10 minutes and was extractedwith methylene chloride. The organic phase was washed with aqueoussaturated sodium chloride solution, was dried and evaporated to dryness.The residue was chromatographed over silica gel was eluted with a 6-4petroleum ether-ethyl acetate mixture to obtain 680 mg of3,3-[1,2-ethanediyl-bisoxy]11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol with a specific rotation of [α]_(D) ²⁰=-76.5°±3° (c=0.5% in chloroform).

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor17α-Δ⁴,9 -pregnadiene-20-yne-17β-ol-3-one

A mixture of 1 ml of 2N hydrochloric acid, 562 mg of product of Step Aand 15 ml of methanol was stirred at temperature for 40 minutes and waspoured into aqueous sodium bicarbonate solution. The mixture wasextracted with ether and the organic phase was washed with aqueoussaturated sodium chloride solution, was dried and evaporated to dryness.The residue was chromatographed over silica gel and was eluted with a6-4 petroleum ether-ethyl acetate mixture to obtain 364 mg of11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17α-Δ⁴,9-pregnadiene -20yne-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+97.5°±3° (c=0.35% in CHCl₃).

Analysis: C₃₁ H₄₁ NO₂ Si; molecular weight=487.76, Calculated: % C76.33,% H 8.47, % N 2.87, Found: 76.4, 8.7, 2.8.

EXAMPLE 45 N-oxide of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)]-.DELTA.⁴,9-estradiene-17β-ol-3-one

A solution of 0.64 g of m-chloroperbenzoic acid in 12.8 ml of methylenechloride was added over 15 minutes at 0° to 5° C. to a solution of 1.4 gof the product of Example 38 in 28 ml of methylene chloride and themixture was stirred at 0° to 5° C. for one hour and was then poured intoaqueous 0.2N sodium thiosulfate solution. The decanted aqueous phase wasextracted with methylene chloride and the organic phase was washed withaqueous sodium bicarbonate solution, dried and evaporated to dryness.The residue was chromatographed over silica gel and was eluted with an8-2 mixture to obtain 1.28 g of N-oxide of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one. The product was dissolved in a mixture ofmethylene chloride and diisopropyl oxide and the mixture was vacuumfiltered to obtain 1.075 g the said product melting at 215° C. andhaving a specific rotation of [α]_(D) ²⁰ =+74.5°±2.5° (c=0.7% in CHCl₃).

EXAMPLE 46 Hemifumarate of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

A mixture of 0.378 g of fumaric acid in 4.54 ml of ethanol was added toa mixture of 1.44 g of the product of Example 38 in 2.88 ml of ethanoland the mixture was stirred at 60° C. for 30 minutes. The mixturereturned to 20° C. and was stirred. The mixture was evaporated todryness and the residue was taken up in ether. The mixture was vacuumfiltered and the product was dried to obtain 1.70 g of hemifumarate of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one melting at 160° C. and having a specificrotation of [α]_(D) ²⁰ =+70.5°±2.5° (c=0.8% in CHCl₃).

EXAMPLE 4711β-[4-(N,N-dipropylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one STEP A: 3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dipropylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁹ -estrene-5α,17β-diol

A solution of 52 g of 4-bromo-N,N-dipropyl-aniline in 110 ml oftetrahydrofuran was added dropwise at 40° C. under an inert atmosphereto a mixture of 5 g of magnesium and 15 ml of anhydrous tetrahydrofuranto obtain a 1.1M magnesium solution. A solution 5.55 g of3,3-[1,2-ethanediyl-bisoxy]-5α,1060 -epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol and 200 mg of cuprous chloride was stirred at 0° to 5°C. and then 50 ml of the magnesium solution were added thereto over 15minutes. The mixture was stirred at 20° C. for one hour and was thenpoured into aqueous saturated ammonium chloride solution. The mixturewas extracted with ether and the organic phase was dried and evaporatedto dryness. The residue was chromatographed over silica gel and waseluted with a 7-3 toluene-ethyl acetate mixture to obtain 6.3 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dipropylamino]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α, 17β-diol with a specific rotation of [α]_(D) ²⁰ =-56°±2°(c=0.8% in CHCl₃).

Analysis: C₃₅ H₄₉ NO₄ ; molecular weight=547.75, Calculated: % C 76.74,% H 9.02, % N 2.56, Found: 76.6, 9.2, 2 5.

STEP B: 11β-[4-(N,N-dipropylamino)-phenyl]-17α-(prop-1-ynyl) -Δ⁴,9-estradiene-17β-ol-3-one

A mixture of 10 ml of 2N hydrochloric acid, 5,83 g of the product ofStep A and 80 ml of methanol was stirred at 20° C. for 50 minutes andwas then neutralized by addition of N sodium hydroxide solution. Themixture was evaporated to dryness under reduced pressure and the residuewas taken up in methylene chloride. The organic phase was washed withwater, dried and evaporated to dryness and the residue waschromatographed over silica gel. Elution with a 3-1 toluene-ethylacetate mixture yielded 3.81 g of11β-[4-(N,N-dipropylamino)-phenyl/-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one.

IR Spectrum: Absorption at 3600 cm⁻¹ (OH); at 1654 cm⁻¹ (C=0); at1610-1595-1558 and 1517 cm⁻¹ (Δ⁴,9 and aromatic bands); at 2240 cm⁻¹(C.tbd.C).

The following products were prepared by the process of the inventionusing the appropriate starting materials:

(A) 11β-[4-(N-ethyl-N-methylamino)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one melting at 174° C. and having a specificrotation of [α]_(D) ²⁰ =+149°±2.5° (c=1% in CHCl₃).

(B) 11β-[N-methyl 2,3-dihydro-1H-indol-5-yl]-17α-(prop-1 ynyl)-Δ⁴,9-estradiene-17β-ol-3-one melting at 176° C. and having a specificrotation of [α]_(D) ²⁰ =+133°±3° (c=0.8% in CHCl₃).

(C) 3-hydroxyimino-11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol (Z isomer) melting at 260° C. and having a specificrotation of [α]_(D) ²⁰ =+141°±3.5° (c=0.8% in CHCl₃) and thecorresponding E isomer melting at 220° C. and having a specific rotationof [α]_(D) ²⁰ =+164°±3.5° (c=0.8% in CHCl₃).

(D) N-oxide of 11β-[4-pyrrolidyl-phenyl]-17α-(prop-1 ynyl)-Δ⁴,9-estradiene-17β-ol-3-one melting at 220° C. and having a specificrotation of [α]_(D) ²⁰ =+88°±2.5° (c=0.75% in CHCl₃).

(E)11β-[4-(N-methyl-N-isopropylamino)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+140°±3.5° (c=0.5% in CHCl₃).

(F) N-oxide of11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =+60.5°(c=1.2% in CHCl₃).

(G) N-oxide of11β-[(N-methyl)-2,3-dihydro-1H-indol-5-yl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+103°±2.5° (c=0.8% in CHCl³).

(H) 11β-[4(N-methyl-N-trimethylsilylmethylamino)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3 one.

(I) 11β-[4-(N-methyl-N-dimethylaminoethylamino)phenyl]-17α-(prop-1-ynyl)-Δ⁴,9 -estradiene-17β-ol-3-one.

(J)11β-[4-(N-methyl-piperazin-1-yl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one.

(K) 11β-[4-(N,N-dimethylamino)-phenyl]-17-hydroxyimino-Δ⁴,9-estradiene-3-one with a specific rotation of [α]_(D) ²⁰ =+207.5°±3.5°(c=1% in CHCl₃).

(L) 3(E)-hydroxyimino- 11β-[4-(N,N-dimethylamino)phenyl]-17-hydroxyimino-Δ⁴,9 -estradiene-3-one with a specific rotationof [α]_(D) ²⁰ =+195°±3° (c=1% in CHCl₃) and its corresponding 3(Z)isomer with a specific rotation of [α]_(D) ²⁰ =+163°±2.5° (c=0.6% inCHCl₃).

EXAMPLE 48 γ-lactone of 11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁴,9-pregnadiene -17β-ol-3-one-21-carboxylic acid STEP A: γ-lactone of3,3-ethylenedioxy-11β-(4-dimethylamino-phenyl)-19-nor-17α-.DELTA.⁹(10)-pregnene-5α,17β-diol-21-carboxylic acid

60 ml of a solution of 15% butyllithium in hexane cooled to -70° C. werediluted with 60 ml of tetrahydrofuran and a solution of 9.2 ml of allylN,N,N',N'-tetramethyl-phosphoramidate in 30 ml of anhydroustetrahydrofuran was added thereto at -60° C. The mixture was held at-15° to -10° C. for 45 minutes and then a solution of 9.95 g of3,3-ethylenedioxy-11β-(4-N,N-dimethylamino-phenyl)-Δ⁹-estrene-5α-ol-17-one(described in Step B of Example 22 in 20 ml ofanhydrous tetrahydrofuran was added thereto. The mixture was rinsed with5 ml of anhydrous tetrahydrofuran and 20 ml of tetrahydrofuran wereadded with stirring. The temperature returned to room temperature overone hour and the mixture was poured into an aqueous ammonium chloridesolution. The mixture was extracted with ethyl acetate and the organicphase was washed with water dried and evaporated to dryness underreduced pressure to obtain 12.95 g of residue which contained startingmaterial. The residue was chromatographed over silica gel and was elutedwith a 3-7 cyclohexane-ethyl acetate mixture to separately obtain 5 g ofstarting material, 0.27 g of a mixture and 3.9 g of γ-lactone of3,3-ethylenedioxy-11β-(4-dimethylamino-phenyl)-19nor-17α-.DELTA.⁹(10)-pregnene-5α,17β-diol-21-carboxylic acid. 5.5 g of the latter weredissolved in methylene chloride and the solution was filtered. Thefiltrate was diluted with isopropyl ether and the solution wasconcentrated by evaporation of methylene chloride to obtain a suspensionof crystals in isopropyl ether from which 4.87 g of the product meltingat 198° C. were recovered.

Analysis: C₃₁ H₄₁ O₅ N: molecular weight=507.67 Calculated: % C 73.34 %H 8.14 % N 2.76 Found: 73.1, 8.3, 2.8.

STEP B: γ-lactone of 11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁴,9-pregnadiene-17β-ol-3-one-21-carboxylic acid

A solution of 4.7 g of the product of Step A in 40 ml of methanol and 10ml of 2N hydrochloric acid stood for one hour at room temperature andwas then diluted with water and was extracted with methylene chloride.The organic phase was washed with water, dried and evaporated to drynessunder reduced pressure. The 4.5 g of residue were chromatographed oversilica gel and eluted with a 4-6 cyclohexane-ethyl acetate mixture toobtain 3.85 g of non-crystalline γ-lactone of11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁴,9-pregnadiene-17β-ol-3-one-21-carboxylic acid with a specific rotation of[α]_(D) ²⁰ =+172° (c=1% in chloroform).

Analysis: C₂₉ H₃₅ NO₃ ; molecular weight=445.61, Calculated: % C 78.17,% H 7.91, % N 3.14, Found: 78.5, 8.1, 3.0.

EXAMPLE 49 γ-lactone of11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ¹,3,5(10)-pregnatriene-3,17β-diol-21-carboxylic acid

1.5 g of palladium hydroxide on magnesium were added to a solution of 1g of the product of Example 48 in 300 ml of methanol and the mixture wasstirred at reflux for one hour and was then cooled and filtered. Thefiltrate was evaporated to dryness to obtain 1 g of a colored product.The latter was chromatographed over silica gel and eluted with a 1-1cyclohexane-ethyl acetate mixture and the 980 mg of product werecrystallized from ether. The suspension was vacuum filtered to obtain715 mg of γ-lactone of11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ¹,3,5(10)-pregnatriene-3,17β-diol-21-carboxylic acid which melted at 311° C.after crystallization from ethyl acetate.

Analysis: C₂₉ H₃₅ NO₃ ; molecular weight=445.6, Calculated: % C 78.15, %H 7.9, % N 3.14, Found: 78.4, 8.0, 3.0.

EXAMPLE 50 γ-lactone of3-methoxy-11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ¹,3,5(10)-pregnatriene-17β-ol-21-carboxylic acid

A solution of diazomethane [prepared by Can. J. Res., Vol. 28 (1950),683] in methylene chloride was added to a solution of 280 mg of theproduct of Example 49 in 3 ml of methylene chloride and the diazomethanewas added again. After 20 hours, acetic acid was added to destroy excessdiazomethane and the mixture was made alkaline by addition of aqueoussodium bicarbonate. The decanted organic phase was washed with water,dried and evaporated to dryness under reduced pressure to obtain 295 mgof a mixture containing starting material. The latter waschromatographed over silica gel and eluted with a 7-3 and then 1-1cyclohexane-ethyl acetate mixture to obtain 120 mg of γ-lactone of3-methoxy-11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ¹,3,5(10)-pregnatriene-17β-ol-21-carboxylic acid and then 140 mg of startingmaterial. The former product was dissolved in methylene chloride and thesolution was filtered. The filtrate was evaporated to dryness and theproduct was crystallized from ether, vacuum filtered and washed withether to obtain 66 mg of desired product melting at 210° C.

Analysis: C₃₀ H₃₅ NO₃ ; molecular weight=459.63, Calculated: % C 78.39,% H 8.11, % N 3.04, Found: 78.2, 8.4, 3.0.

EXAMPLE 51 γ-lactone of 11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁵(10)-pregnene-17β-ol-3-one-21-carboxylic acid

1 ml of a 1.3M of lithium tert.-butanolate in tetrahydrofuran and 1 mlof water were added to a solution of 690 mg of the γ-lactone of11β-(4-dimethylamino-phenyl)-19-nor-α-Δ⁴,9(10)-pregnadiene-17β-ol-3-one-21-carboxylic acid in 10 ml of absolute ethanol and themixture was refluxed under nitrogen for 30 minutes. The mixture wasevaporated to dryness under reduced pressure and the residue was takenup in benzene. The solution was distilled to dryness and the lithiumsalt was dissolved in a mixture of 9 ml of tetrahydrofuran and 1 ml oftert.-butanol. The said solution was added to 30 ml of ammonia cooled to-70° C. and the solution was rinsed with 3 ml of anhydroustetrahydrofuran. 24 mg of lithium were added to the solution whilemaintaining an internal temperature of -50° to -60° C. The ammonia wasdistilled and the mixture was acidified with hydrochloric acid. Theresulting solution stood at room temperature for 30 minutes and was madealkaline by addition of a sodium bicarbonate solution. The mixture wasextracted with methylene chloride and the organic phase was washed withwater, dried and evaporated to dryness to obtain 680 mg of residue. Thelatter was chromatographed over silica gel and eluted with a 7 to 3 andthen 1 to 1 mixture of cyclohexane-ethyl acetate to obtain 505 mg ofnon-crystalline γ-lactone of11β-(4-dimethylamino-phenyl)-19-nor-17α-Δ⁵(10)-pregnene-17β-ol-3-one-21-carboxylic acid.

NMR Spectra (CDCl₃): Peaks at 0.53 (13-methyl); at 2.9 (methyls ofdimethylamino); at 3.51 (11-hydrogen).

Analysis: C₂₉ H₃₇ NO₃, Calculated: % C 77.81, % H 8.33, % N 3.13, Found:77.5, 8.6, 3.0.

EXAMPLE 52

Tablets were prepared containing 50 mg of the product of Example 19 andsufficient excipient of talc, starch and magnesium stearate for a finaltablet weight of 120 mg.

EXAMPLE 53

Tablets were prepared containing 50 mg of the product of Example 5 andsufficient excipient of talc, starch and magnesium stearate for a finalweight of 120 mg.

PHARMACOLOGICAL STUDY I. Activity of products on hormonal receptors A.Mineralcorticoidal receptor of kidneys of the rat

Male Sprague-Dawley EOPS rats weighing 140 to 160 g surrenalectomized 4to 8 days previously were killed and their kidneys were perfused in situwith 50 ml of a buffer (10 mM of Tris 0.25M of Saccharose and sufficienthydrochloric acid for a pH of 7.4). The kidneys were then removed,decapsulated and homogenized at 0° C. with apolytetrafluoroethylene-glass Potter (1 g of tissue per 3 ml of buffer).The homogenate was centrifuged for 10 minutes at 800 g at 9° C.

After elimination of the fixation of tritiated aldosterone withglucocorticoid receptor, 21-methyl-Δ¹,4,6-pregnatriene-20-yne-11β,17β-diol-3-one fixed only with theglucocorticoid receptor was added to the supernatant at a finalconcentration of 10⁻⁶ M. The suprenatant was ultracentrifuged at 105,000g for 60 minutes and 0° C. and aliquoits of the resulting surnageantwere incubated at 0° C. with a constant concentration (T) of tritiatedaldosterone in the presence of increasing concentrations (0-2500×10⁻⁹ M)of cold aldosterone or the cold test product. After a time (t) ofincubation, the concentration of tied tritiated aldosterone (B) wasmeasured by the technique of adsorption on carbon dextran.

B. Androgen receptor of prostate of rats

Male Sprague-Dawley EPOS rats weighing of 160 to 200 g were castratedand 24 hours later, the animals were killed. The prostates were removed,weighed and homogenized at 0° C. with a polytetrafluoroethylene-glassPotter with a buffered TS solution (Tris, 10 mM, 0.25M Saccharose,HCl-pH of 7.4) using 1 g of tissue per 5 ml of TS. The homogenate wasthen ultracentrifuged at 105,000 g for 60 minutes at 0° C. and aliquoitsof the resulting supernatant were incubated at 0° C. for 2 hours with aconstant concentration (T) of product P or 17α-methyl-Δ⁴,9,11-estratriene-17β-ol-3-one in the presence of increasing concentration(0-1,000×10⁻⁹ M) of either cold P, cold testosterone or the testcompound. The concentration of tied tritiated (B) was measured for eachincubate by the technique of adsorption on carbon-dextran.

C. Progestogen receptor of the uterus of rabbits

Immature rabbits weighing about 1 kg received a cutaneous application of25 μg of estradiol and the animals were killed 5 days later. The uteruswas removed, weighed and homogenized at 0° C. with apolytetrafluoroethylene-glass Potter, in a buffered TS solution [Tris10. mM, 0.25M of saccharose, HCl-pH of 7.4] with 1 g of tissue per 50 mlof TS. The homogenate was ultracentrifuged at 105,000 g for 90 minutesat 0° C. and aliquoits of the resulting supernatant were incubated at 0°C. for a time (t) with a constant concentration (T) of tritiated productR or 17,21-dimethyl-19-nor-Δ⁴,9 -pregnadiene-3,20-dione in the presenceof increasing concentrations (0 to 2500×10⁻⁹ M) of either cold R, coldprogesterone or cold test compound. The concentration of tied tritiatedR (B) was then measured for each incubate by the technique of adsorptionon carbondextran.

D. Gluocorticoid receptor of thymus of rats

Male Sprague-Dawley EPOS rats weighing 160 to 200 g weresurrenalectomized and the animals were killed 4 to 8 days later. Thethymus were removed and homogenized at 0° C. in a buffered TS solutionof 10mM, Tris, 0.25M of Saccharose, 2 mM of dithiothreitol HCl for a pHof 7.4 using a polytetrafluoroethylene-glass Potter at a rate of 1 g oftissue per 10 ml of TS. The homogenate was ultra-centrifuged at 105,000g for 90 minutes at 0° C. and aliquoits of the resulting surnageant wereincubated at 0° C. for a time (t) with a constant concentration (T) oftritiated dexamethasone in the presence of an increasing concentration(0 to 2500×10⁻⁹ M) of either cold dexamethasone or cold test product.The concentration of tied tritiated dexamethasone (B) was measured foreach incubate by the adsorption on carbon-dextran technique.

E. Estrogen receptor of uterus of mice

Immature female mice 18 to 21 days old were killed and the uterus wereremoved and homogenized at 0° C. with a polytetrafluoroethylene-glassPotter in a buffered TS solution consisting of 10 mM, Tris, 0125MSaccharose, HCl for a pH of 7.4 at a rate of 1 g of tissue per 25 ml ofTS. The homogenate was then ultracentrigued at 105,000 g for 90 minutesat 0° C. and aliquoits of the resulting tritiated were incubated at 0°C. for a time (t) with a constant concentration (T) of tritiatedestradiol in the presence of increasing concentrations (0 to 1000×10⁻⁹M) of either cold estradiol or cold test compound. The concentration oftied tritiated estradiol (B) was measured for each incubate by thetechnique of adsorption on carbon-dextran.

The calculation of the relative affinity of concentration (ARL) wasidentical for all of the above receptor tests. One traced the followingtwo curves the percentage of tied tritiated hormone ##EQU1## as afunction of the logarithm of the cold hormone concentration and ##EQU2##as a function of the logarithm of the concentration of the cold testproduct. One determined the line of the equation. ##EQU3## is thepercentage of tied tritiated hormone for an incubation of the hormone atconcentration T ##EQU4## is the percentage of tied tritiated hormone foran incubation of the tritiated hormone at a concentration (T) in thepresence of a large excess of cold hormone (2500×10⁻⁹ M).

The intersection of the I₅₀ line and the curves permits one to determinethe concentrations of the cold hormone of the reference (CH) and thecold test compound (CX) which inhibit by 50% the tieing of tritiatedhormone with the receptor. The relative affinity of tieing (ARL) of thetest product was determined by the equation: ##EQU5## The results arereported in the following Table.

    __________________________________________________________________________    Mineralo                Pro-     Gluco-                                       corticoid      Androgen gestogen corticoid                                                                              Estrogen                            Product of                                                                          Time of incubation at 0° C.      5 H                             Example                                                                             1 H  24 H                                                                              1/2 H                                                                              24 H                                                                              2 H  24 H                                                                              4 H  24 H                                                                              2 H (25° C.)                 __________________________________________________________________________     1    <0,1 <0,1                                                                              --   --   4    4  97    38 <0,1                                                                              <0,1                             2 (17 OH)                                                                           0,2 <0,1                                                                              *    *   39   130 153  222  5  <0,1                             2 (17 OAc)                                                                         <0,1 <0,1                                                                              <0,1 <0,1                                                                               5   52  58   100 <0,1                                                                               0,3                             5 (2α)                                                                       <0,1 <0,1                                                                               0,5  0,4                                                                              40   39  214  255 <0,1                                                                              <0,1                             5 (2β)                                                                        <0,1 <0,1                                                                               0,7  0,5                                                                              44   44  224  299 <0,1                                                                              <0,1                             9    <0,1 <0,1                                                                              <0,1 <0,1                                                                              <0,1 <0,1                                                                              14    7  <0,1                                                                              <0,1                            10     1,5 <0,1                                                                              --   --  27   62  83   115 <0,1                                                                              <0,1                            13    --   --  5    6   --   --  3,9  --  78  239                             14    --   --  10,6 0,5 --   --  0,4  --  4,1 1,4                             15    --   --   1,3 0,2 --   --   2   --  0,1 0,1                             __________________________________________________________________________    Mineralo                         Gluco-                                       corticoid      Androgen Progestogen                                                                            corticoid                                                                              Estrogen                            Product of                                                                          Time of incubation at 0° C.                                      example                                                                             2 H                                                                              4 H                                                                              24 H                                                                             2 H                                                                              4 H                                                                              24 H                                                                             2 H                                                                              4 H                                                                              24 H                                                                             2 H                                                                              4 H                                                                              24 H                                                                             2 H                                                                              4 H                                                                              24 H                          __________________________________________________________________________    19    -- -- 0  -- -- 20 74 -- 640                                                                              -- 270                                                                              265                                                                              0  -- --                            32    -- -- 0  -- -- 68 81 -- 351                                                                              -- 279                                                                              235                                                                              0  -- --                            29    -- -- -- -- --  0 41 -- 250                                                                              --  46                                                                               94                                                                              0  -- --                            23    -- -- 0  -- -- 14,7                                                                             81 -- 268                                                                              -- 212                                                                              167                                                                              0  -- --                            25    -- -- 0  -- -- 32 78 -- 467                                                                              -- 254                                                                              292                                                                              0  -- --                            26    -- -- 0  -- -- 9,8                                                                              6,3                                                                              -- 8,3                                                                              --  9  14                                                                              0  -- --                            31    -- -- 1,7                                                                              -- -- 29 129                                                                              -- 166                                                                              -- 283                                                                              259                                                                              0  -- --                            27    -- -- 0  -- -- 2,8                                                                              0,6                                                                              -- 0,4                                                                              -- 5,3                                                                              6,2                                                                              0  -- --                            21    -- -- 0,8                                                                              -- -- 7,3                                                                              10 -- 4,3                                                                              -- 171                                                                              118                                                                              0  -- --                            35    -- -- -- -- -- 2,2                                                                              1,1                                                                              -- 2,5                                                                              -- 7,8                                                                               5 0  -- --                            37    -- -- 0,3                                                                              -- --  8 175                                                                              -- 843                                                                              -- 178                                                                              221                                                                              0  -- --                            44    -- -- 0  -- -- 4,6                                                                              15,2                                                                             --  38                                                                              --  79                                                                              104                                                                              0  -- --                            __________________________________________________________________________     *The product presented an affinity for the receptor.                     

CONCLUSION

The tested compounds and especially those of Examples 2, 5,19,25,31,32and 37 present a very remarkable affinity for glucocorticoid andprogestogen receptors as well as a slightly moderate affinity forandrogen receptors. These results lead to the conclusion that theproducts do not have any mineralcorticoid and estrogen receptors andpresent an agonist or antagonistic activity to glucocorticoids,progestogens and androgens. Moreover, the products of Examples 13 and 14present an agonist or antagonistic activity to estrogens.

II. Anti-inflammatory Activity

The anti-inflammatory activity of the compound of Example 4 wasdetermined by the classical granuloma test by a modification of theMeier at al test [Experientia, vol. 6 (1950), p. 469] in which normalfemale Wistar rats weighing 100 to 110 g received an implantation of 2pellets of cotton weighing 10 mg each under the thorax skin. Thesubcutaneous treatment which began immediately after the implantationfor 2 days was 2 injections per day. 16 hours after the last injection,the animals were killed and the pellets together with the granulomatissue formed were weighed in the fresh state and after 16 hours at 60°C. The weight of the granuloma was obtained by subtracting the initialweight of the cotton. The thymus was also removed and weighed todetermine the thymolytic activity of the test product.

At a subcutaneous dose of 50 mg/kg, the product of Example 19 did notshow any glucocorticoidal anti-inflammatory activity or thymolyticactivity.

III. Antiglucocorticoidal Activity

The test used was that of Dausse et al [Molecular Pharmacology, Vol. 13(1977), p. 948-955] entitled "The relationship between glucocorticoidstructure and effects upon thymocytes" for mice thymocytes. Thethymocytes of surrenalectomized rats were incubated at 37° C. for 3hours in a nutritive medium containing 5×10⁻⁸ M of dexamethasone in thepresence or absence of the test compound at different concentrations.Tritiated uridine was added and incubation was continued for one hour.The incubates were cooled and treated with a 5% trifluoroacetic acidsolution and the mixture was filtered with Whatman GF/A paper. Thefilter was washed 3 times with a 5% trifluoroacetic acid solution andretained radioactivity on the filter was determined. Glucocorticoids andespecially dexamethasone provoked a lessening of incorporation oftritiated uridine and the tested compounds, especially those of Examples1,2,5 10,19,21,23,25,26,29,31, 35 and 37 opposed this effect as can beseen from the following Table.

    ______________________________________                                                 5 × 10.sup.-8 of Dexametha-                                                              % inhibition of                                     Product of                                                                             sone + test product                                                                            effect of Dexametha-                                Example  in concentration of                                                                            sone                                                ______________________________________                                        1        10.sup.-8 M       8                                                           10.sup.-7 M      18                                                           10.sup.-6 M      *                                                   2 (17 OH)                                                                              10.sup.-8 M      41                                                           10.sup.-7 M      91                                                           10.sup.-6 M      *                                                   2 (17 OAc)                                                                             10.sup.-8 M      24                                                           10.sup.-7 M      76                                                           10.sup.-6 M      *                                                   3        10.sup.-8 M       0                                                           10.sup.-7 M       0                                                           10.sup.-6 M      60                                                  4        10.sup.-8 M       0                                                           10.sup.-7 M       0                                                           10.sup.-6 M      51                                                  5 (2α)                                                                           10.sup.-8 M      19                                                           10.sup.-7 M      57                                                           10.sup.-6 M      100                                                 5 (2β)                                                                            10.sup.-8 M      10                                                           10.sup.-7 M      57                                                           10.sup.-6 M      *                                                   7        10.sup.-8 M       0                                                           10.sup.-7 M      27                                                           10.sup.-6 M      *                                                   9        10.sup.-8 M       3                                                           10.sup.-7 M       1                                                           10.sup.-6 M       2                                                  10       10.sup.-8 M       0                                                           10.sup.-7 M      23                                                           10.sup.-6 M      *                                                   6        10.sup.-8 M       0                                                           10.sup.-7 M       0                                                           10.sup.-6 M      68                                                  6 (17α prope-                                                                    10.sup.-8 M       0                                                  nyle)    10.sup.-7 M       0                                                           10.sup.-6        56                                                  19       10.sup.-8 M      30                                                           10.sup.-7 M      70                                                           10.sup.-6 M      90                                                  29       10.sup.-8 M      18                                                           10.sup.-7 M      57                                                           10.sup.-6 M      *                                                   23       10.sup.-8 M      22                                                           10.sup.-7 M      53                                                           10.sup.-6 M      *                                                   25       10.sup.-8 M      57                                                           10.sup.-7 M      85                                                           10.sup.-6 M      *                                                   26       10.sup.-8 M      14                                                           10.sup.-7 M      34                                                           10.sup.-6 M      75                                                  31       10.sup.-8 M      28                                                           10.sup.-7 M      60                                                           10.sup.-6 M      99                                                  21       10.sup.-8 M       5                                                           10.sup.-7 M      15                                                           10.sup. -6 M     83                                                  35       10.sup.-8 M       4                                                           10.sup.-7 M      21                                                           10.sup.-6 M      50                                                  37       10.sup.-8 M      16                                                           10.sup.-7 M      69                                                           10.sup.-6 M      *                                                   ______________________________________                                         *A dose of 10.sup.-6 M inhibited totally the effect of dexamethasone          totally                                                                  

CONCLUSION

The products of the invention used alone do not provoke any effect ofthe glucocorticoid type at doses provoking an antiagonist agonist effectand the tested products present a very remarkable antiglucocorticoidactivity and are devoid of any glucocorticoid activity.

IV. Progestomimetic and Anti-progestomimetic Activity

(a) Groups of immature female rabbits weighing about 1 kg hadadministered to them subcutaneously from day 1 to day 5, 5 μg ofestradiol. The product tested was afterward administered orally from day8 to day 11 in a volume of 0.5 cm³ of water containing 0.5% ofcarboxymethyl cellulose and 0.2% of Tween. On day 12, the rabbits weresacrificed, their uteruses were retained and fixed in Bouin's solutionand histologically studied.

The changes in the uterine endometrium were noted according to themethod of McPhail. Only superior results or those equal to two units ofMcPhail were considered significant.

The following results were obtained.

    ______________________________________                                                                 CHANGE IN THE                                                      DOSAGE     ENDOMETRIUM IN                                       TREATMENT     mg/kg      McPHAIL UNTS                                         ______________________________________                                        Progesterone  0.2        3.2                                                  (subcutaneously)                                                              Product of Example                                                                          0.3        0                                                    19 (by mouth) 1.0        0                                                    (RU 38486 or RU 486)                                                                        3.0        0                                                                  10.0       0                                                                  50         0                                                    Progesterone  0.2        3.0                                                  (subcutaneously)                                                              Progesterone 0.2 mg                                                                         0.3        2.8                                                  (subcutaneously) +                                                                          1          2.1                                                  the compound of                                                                             3          1.4                                                  example 19 (by mouth)                                                                       10         0.6                                                                20         0                                                    ______________________________________                                    

Groups of three immature female rabbits weighing about 1 kg weretopically treated on the dorsal skin with 25 μg of estradiol in 10 μl ofethanol on day 1. On day 4 the product to be tested dissolved in 0.1 mlof sesame oil containing 5% benzyl alcohol was introduced into a part ofthe uterus isolated between two ligatures. On the sixth day the animalswere sacrificed, their uteruses retained and fixed in Boun's solutionfor histological examination. Changes in the uterine endometrium werenoted after the method of McPhail.

The following results were obtained.

    ______________________________________                                                       DOSE μg/                                                                              CHANGE IN THE                                       TREATMENT      RABBIT     ENDOMETRIUM                                         ______________________________________                                        Product of Example 19                                                                        30         0                                                                  500        0                                                   Progesterone   10         2.7                                                 Progesterone 10 μg +                                                       Product of Example 19                                                                        1          1.6                                                                3          1.3                                                                10         1.0                                                                30         0.6                                                                90         0.6                                                 ______________________________________                                    

Conclusion:

This product tested is devoid of progestomimetic activity while on thecontrary it possesses a remarkable antiprogestomimetic activity.

V. ANTI-IMPLANTATION AND ABORTIVE ACTIVITIES IN FEMALE RATS

The first day of gestation is determined by the presence of sperm in thevagina. The product of example 19 is administered by mouth 3 consecutivedays at the rate of 5 ml per kilogram as a suspension of 0.5% ofcarboxymethyl cellulose in water containing 0.2% Tween.

The animals were sacrificed between the 5th and 8th day after the lasttreatment and the uterus was examined.

The following results were obtained:

    ______________________________________                                        DAYS OF                                                                       TREATMENT  DOSE mg/kg/day RESULTS                                             ______________________________________                                        1,2,3      10             Non-implantation                                      "        2              No action                                           4,5,6      10             Non-implantation                                      "        2              Non-implantation                                    7,8,9      10             Abortion                                              "        2              Abortion                                            10,11,12   10             Abortion                                              "        2              Abortion                                            13,14,15   10             Abortion                                              "        2              Abortion in 50% of                                                            the animals                                         ______________________________________                                    

Conclusion:

This product tested showed anti-implantation activity and abortiveactivity in the rat at all times of the period of gestation.

Various modifications of the products and methods of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is intended to be limited only asdefined in the appended claims.

What we claim is:
 1. A compound selected from the group consisting of19-nor-steroids of the formula ##STR537## wherein R₁ is an organic groupof 1 to 18 carbon atoms containing at least one atom selected from thegroup consisting of oxygen, sulfur and nitrogen with the atomimmediately adjacent the 11-carbon atom being carbon, R₂ is ahydro-carbon 1 to 8 carbon atoms, the A and B rings are selected fromthe group consisting of ##STR538## R' and R" are individually selectedfrom the group consisting of hydrogen, --CN and alkyl of 1 to 4 carbonatoms, R_(a) may be in th E or Z positions as indicated by the wavy lineand is selected from the group consisting of ##STR539## and acyloxy,R'_(a) and R"_(a) are alkyl of 1 to 4 carbon atoms and their non-toxic,pharmaceutically acceptable acid addition salts.
 2. A compound of claim1 wherein R₁ is aryl or aralkyl carrying an amino of the formula##STR540## wherein R₇ and R₈ are alkyl of 1 to 8 carbon atoms orprimary, secondary or tertiary alkyl of 1 to 8 carbon atoms containingat least one heteroatom of the group consisting of --O--, --S-- or --N--with at least one being nitrogen.
 3. A compound of claim 1 wherein R₁ isselected from the group consisting of ##STR541##
 4. A compound of claim1 wherein R₁ is ##STR542##
 5. A compound of claim 1 wherein R₂ ismethyl.
 6. A compound of claim 1 wherein the A and B rings are selectedfrom the group consisting of ##STR543##
 7. A compound of claim 1 whereinthe A and B rings are ##STR544##
 8. A compound of claim 1 wherein R₁ is##STR545## R₂ is methyl and the A and B rings are: ##STR546##
 9. Anantiprogestomimetic composition comprising an antiprogestomimeticallyeffective amount of at least one compound of claim 1 and an inertcarrier.
 10. A composition of claim 9 wherein R₁ is ##STR547## R₂ ismethyl and the A and B rings are ##STR548##
 11. A method of interruptingpregnancy comprising administering to warm-blooded animals anantiprogestomimetically effective amount of the compound of claim 10.12. A method of inducing menses in warm-blooded animals comprisingadministering to warm-blooded animals when progesterone plays aphysiologically essential role, an antiprogestomimetically effectiveamount of at least one compound of claim
 1. 13. A method of claim 12comprising administering to women an antiprogestomimetically effectiveamount of at least one compound of claim 1 during the luteral phase. 14.A method of claim 13 wherein the compound is administered at the end ofluteral phase.
 15. A method of claim 13 wherein the compound isadministered orally or locally.
 16. A method of claim 12 wherein thecompound is administered orally or locally.
 17. A method of claim 12wherein the compound is administered during 1 to 5 days.
 18. A method ofinterrupting pregnancy comprising administering to warm-blooded animalsan antiprogestomimetically effective amount of at least one compound ofclaim 1.